Hydroxyurea | Pharmacology Mentor

Generic Name

Hydroxyurea

Mechanism

Inhibition of ribonucleotide reductase (RR) – HU reduces deoxyribonucleotide triphosphates, impairing DNA synthesis and elongation in rapidly dividing cells.
Induction of fetal hemoglobin (HbF) – Upregulates γ‑globin transcription via nitric oxide (NO) production and activation of soluble guanylate cyclase, raising HbF levels that ameliorate sickling.
β‑cell apoptosis and cell cycle arrest – In myeloproliferative disorders, HU causes G0/G1 arrest, limiting clonal proliferation.
Nitric oxide (NO) scavenger – Lowers NO availability, contributing to vasodilation and altered leukocyte adhesion (clinically relevant in SCD).

> *Key point:* HU’s dual anti‑proliferative and HbF‑inducible actions underpin its therapeutic versatility.

Pharmacokinetics

Absorption – Oral bioavailability ~ 70%; peak plasma concentration within 30‑60 min.
Distribution – Extensively distributed to hematopoietic tissues; protein binding low (~5–10 %).
Metabolism – Minimal hepatic metabolism; largely unchanged in plasma.
Elimination – Renal excretion (≈ 70 % unchanged; rest as metabolites); t½ ≈ 4.6 h.
Special populations – Dose adjustment not routinely required for mild‑moderate renal impairment; caution in severe CKD (eGFR *Practice tip:* Administer HU at the same time each day to minimize peak‑to‑peak variability.

Indications

Sickle cell disease – Reduces vaso‑occlusive crises (VOC) and steady‑state pain.
Myeloproliferative neoplasms – Essential thrombocythemia (ET), polycythemia vera (PV), chronic myelogenous leukemia (CML) (in combination with tyrosine‑kinase inhibitors).
Chronic granulocytic leukemia – Adjunctive therapy in early disease.
Leukemia relapse – Occasionally used for blast clearance pre‑transplant.

Condition	Typical Use
SCD	Primary prophylaxis for VOC and acute chest syndrome (ACS).
ET/PV	Cytoreduction with or without hydroxyurea‑induced splenomegaly control.

Contraindications

Absolute contraindications:
Pregnancy (Category X; teratogenic).
Active uncontrolled infection.
Severe hepatic impairment.
Relative warnings:
Renal dysfunction – Monitor renal function; consider dose reduction.
Pre‑existing cytopenias – Risk of myelosuppression; require baseline CBC.
Potential for secondary malignancies – Monitor for solid cancers (e.g., breast, colorectal) in long‑term therapy.
Drug interactions:
Immunosuppressants (e.g., tacrolimus) – Enhanced myelosuppression.
Chemotherapeutic agents (e.g., 6‑mercaptopurine, cytarabine) – Additive toxicity.

Dosing

Population	Starting Dose	Target Dose	Administration
Adults, SCD	15 mg/kg/day (max 1.5 g/day)	15–35 mg/kg/day (maintain HbF ↑ 1–2 %)	Oral, split 2–3 times daily
Adults, ET/PV	150–200 mg BID	150–800 mg total/day (titrated to platelet count <400 × 10⁹/L)	Oral, divided doses
Patients <50 kg	5 mg/kg/day	200–400 mg/day	Oral

• Slow titration (increment 5–10 mg/day) to mitigate myelosuppression.
• Adherence strategies – Use pill organizers; set daily alarms.

Adverse Effects

Adverse Effect	Incidence	Notes
Myelosuppression (neutropenia, thrombocytopenia)	20–50 %	Dose‑related; monitor CBC biweekly.
Gastrointestinal (nausea, vomiting, diarrhea)	10–20 %	Antiemetic prophylaxis if needed.
Dermatologic (rash, photosensitivity)	5–10 %	Use sun protection; discontinue if severe.
Teratogenicity	High	Contraindicated in pregnancy; use effective contraception.
Secondary malignancies (breast, colorectal)	Low (≈1–2 %/year with prolonged therapy)	Annual screenings advisable.
Pancreatitis	Rare	Monitor abdominal pain; prompt evaluation.
Headache, dizziness	5–15 %	Dose adjustment may reduce symptoms.

> Severe reactions: Hypersensitivity rash, severe neutropenic fever, and alopecia warrant immediate medical assessment.

Monitoring

Baseline – CBC (WBC, Hgb, platelets), CMP (renal/liver), pregnancy test, HbF%, LDH.
Frequency
First 3 months: CBC every 2 weeks.
Maintenance: CBC every 4 weeks (SCD), every 2–4 weeks (ET/PV).
Renal & hepatic: CMP every 3 months; adjust dose if >30% decline in eGFR.
HbF: Every 3–6 months (SCD).
Long‑term surveillance – Annual mammogram (women), colonoscopy (≥40 yr), dermatologic exam.

Clinical Pearls

Pearl 1: “Hydroxyurea as an HbF booster.”
*Tip:* Achieving an HbF >15 % correlates with 70 % reduction in VOC; titrate until this threshold is met.
Pearl 2: “Split dosing improves tolerability.”
*Tip:* Dividing daily dose (e.g., BID or TID) reduces GI upset and myelosuppression peaks.
Pearl 3: “Use in SCD even when transfusion‑compatible.”
*Tip:* Hydroxyurea is safe in patients receiving chronic transfusions; monitor iron overload separately.
Pearl 4: “Avoid concomitant NSAIDs with photosensitive individuals.”
*Tip:* NSAIDs can worsen photosensitivity rash; counsel patients to use broad‑spectrum SPF ≥50.
Pearl 5: “Pregnancy‑safe contraception.”
*Tip:* Teach patients combined oral contraceptives or long‑acting reversible methods; HU therapy is contraindicated in pregnancy.
Pearl 6: “Monitoring for solid tumors.”
*Tip:* Consider colonoscopy starting at age 40 or 10 years earlier than family history, and breast screening in women ≥40 yrs.

> Bottom line: Hydroxyurea remains a first‑line, evidence‑based option for SCD and myeloproliferative disorders, provided clinicians vigilantly monitor cytopenias, renal function, and potential teratogenic risks.