Sickle Cell Disease Pharmacotherapy

Sickle cell disease treatment aims to prevent complications (pain crises, acute chest syndrome, stroke, infection), relieve acute pain and reduce organ damage. Disease-modifying drugs include hydroxycarbamide, L-glutamine, crizanlizumab and voxelotor, though availability varies. Penicillin prophylaxis, malaria prophylaxis, folic acid, vaccination and transfusion remain the foundation of care in much of Africa.

Mechanism. Hydroxycarbamide (hydroxyurea) raises fetal haemoglobin, which blocks sickle haemoglobin polymerisation, and lowers white cell and platelet counts and cell adhesion. Crizanlizumab binds P-selectin and reduces vaso-occlusion. L-glutamine lowers oxidative stress. Voxelotor raised haemoglobin oxygen affinity but was withdrawn in several regions.

Pharmacokinetics. Hydroxycarbamide is well absorbed orally; half-life 3 to 4 hours; 50% renal excretion; fetal haemoglobin rises over 3 to 6 months.

Hydroxycarbamide.

• Start 15 to 20 mg/kg once daily (10 mg/kg in renal impairment).
• Increase by 5 mg/kg every 8 to 12 weeks, while the neutrophil count stays at least 1.5 x 10^9/L (at least 1.0 x 10^9/L in infants and young children), platelets at least 80 x 10^9/L and haemoglobin stable.
• Maximum 35 mg/kg daily; typical dose 20 to 30 mg/kg.
• Offer from 9 months of age to all children with sickle cell anaemia (HbSS or HbS beta zero) whatever the severity.

Other disease-modifying drugs. L-glutamine 5 to 15 g twice daily by weight; crizanlizumab 5 mg/kg intravenously at weeks 0 and 2, then every 4 weeks; regular transfusion or exchange (specialist) for primary and secondary stroke prevention.

Supportive drugs.

• Folic acid 5 mg daily (1 mg in young children).
• Penicillin V 125 mg twice daily (under 3 years), 250 mg twice daily (3 to 5 years) to age 5, then as advised locally.
• Malaria chemoprevention where endemic.
• Vaccination: pneumococcal, meningococcal, Haemophilus influenzae type b, hepatitis B, influenza.

Acute pain. Early analgesia within 30 minutes: paracetamol and NSAIDs for mild pain; oral morphine 0.2 to 0.4 mg/kg or intravenous morphine 0.1 mg/kg (titrated every 15 to 20 minutes) for severe pain; reassess frequently; hydration with oral fluids (avoid excess intravenous fluid); warmth; incentive spirometry. Avoid pethidine.

• First-line. Hydroxycarbamide for recurrent pain, acute chest syndrome, stroke risk, severe anaemia; penicillin prophylaxis, folic acid, vaccines and malaria prevention for all.
• Alternative. L-glutamine or crizanlizumab when hydroxycarbamide fails, is not tolerated or is refused (limited availability).
• Specialist. Regular transfusion for stroke prevention, transcranial Doppler abnormality or intolerance of hydroxycarbamide; stem cell transplant and gene therapy at specialist centres.
• Emergency. Acute chest syndrome (oxygen, analgesia, antibiotics, transfusion), stroke, priapism, splenic sequestration, aplastic crisis, and fever over 38.5 degrees Celsius (immediate antibiotics, e.g. ceftriaxone 50 to 80 mg/kg).

Selection. Begin hydroxycarbamide early in children with HbSS; where laboratory monitoring is unreliable use a lower fixed dose (about 15 to 20 mg/kg) with periodic blood counts.

Contraindications. Hydroxycarbamide: pregnancy and breastfeeding (stop before conception, men and women), severe marrow suppression, hypersensitivity. Avoid pethidine, and avoid dehydration, cold exposure and unnecessary transfusion to haemoglobin over 100 g/L.

Serious adverse effects. Hydroxycarbamide: neutropenia, thrombocytopenia, anaemia, reticulocytopenia, skin and nail pigmentation, mouth ulcers, gastrointestinal upset and (rarely) skin cancer; reversible low sperm count; teratogenic. Crizanlizumab: infusion reactions, headache, arthralgia.

Major interactions. Zidovudine and other myelosuppressive drugs; didanosine and stavudine (pancreatitis, hepatotoxicity); live vaccines; NSAIDs with renal impairment.

Common prescribing errors.

• Starting hydroxycarbamide without a blood count.
• Underdosing out of fear of toxicity.
• Missing penicillin prophylaxis and vaccines.
• Giving pethidine for pain.
• Delayed analgesia and over-hydration.

Special groups.

• Pregnancy: stop hydroxycarbamide before conception; aspirin and low-molecular-weight heparin as indicated; folic acid 5 mg.
• Breastfeeding: avoid hydroxycarbamide.
• Children: weight-based doses; start at 9 months or older; regular growth checks.
• Older adults: renal and cardiac disease; adjust doses.
• Kidney: reduce hydroxycarbamide to 10 mg/kg for creatinine clearance under 60 mL/min; avoid NSAIDs.
• Liver: cautious with hepatic disease.
• East Africa: sickle cell disease is common, with a high childhood burden; malaria chemoprevention and early antibiotics for fever save lives; hydroxycarbamide has been shown safe in African children and should be considered widely; newer agents are seldom available.

Monitoring. Full blood count every 4 weeks during dose escalation, then every 2 to 3 months; reticulocytes; fetal haemoglobin; liver and renal function; growth; transcranial Doppler in children where available; hearing and eye checks.

Referral and escalation. Chest pain with fever or hypoxia; neurological symptoms; priapism over 4 hours; fever; severe pain unresponsive to opioids; falling haemoglobin; pregnancy.

Comparison with alternative classes. Hydroxycarbamide is cheap, oral and reduces crises, hospitalisation and mortality. Transfusion is faster but carries iron overload and alloimmunisation risk; newer agents have limited access and cost.