Usage
Sulphadoxine is an ultra-long-acting sulfonamide antibiotic primarily used in combination with Pyrimethamine, an antiparasitic, for the prevention and treatment of malaria. It’s particularly relevant in regions where chloroquine-resistant strains of Plasmodium falciparum prevail. It is also used for the prophylaxis of Pneumocystis jirovecii pneumonia (PCP) when other options are unsuitable. It belongs to the sulfonamide antibiotic and antimalarial classifications.
Sulphadoxine works by inhibiting dihydropteroate synthase, a crucial enzyme in the folic acid synthesis pathway of the malaria parasite. This disruption of folic acid production hinders the parasite’s growth and replication.
Alternate Names
Sulphadoxine is also known as Sulformethoxine or Sulphormethoxine. A common brand name for the combination of Sulphadoxine and Pyrimethamine is Fansidar®.
How It Works
Pharmacodynamics: Sulphadoxine disrupts the malaria parasite’s folic acid synthesis by competitively inhibiting dihydropteroate synthase. This enzyme is essential for the parasite’s growth and survival. When combined with Pyrimethamine, which inhibits dihydrofolate reductase, another key enzyme in the same pathway, the synergistic effect enhances the antimalarial action.
Pharmacokinetics: Sulphadoxine exhibits excellent oral absorption (>90% bioavailability). It has a large volume of distribution (0.14 L/kg) and high plasma protein binding (around 90%). It undergoes some hepatic metabolism (acetylation and glucuronidation) but primarily exists unchanged in plasma. Sulphadoxine has a very long elimination half-life (approximately 200 hours), contributing to its extended duration of action. It is primarily excreted through renal pathways.
Mode of Action: Sulphadoxine acts by mimicking para-aminobenzoic acid (PABA), a substrate of dihydropteroate synthase. This competitive inhibition prevents the enzyme from incorporating PABA into dihydropteroic acid, a precursor for folic acid. The resulting folate deficiency inhibits the synthesis of nucleic acids and essential metabolites in the parasite, leading to its demise.
Elimination Pathways: Sulphadoxine is primarily eliminated through renal excretion. A smaller portion undergoes hepatic metabolism, with around 5% appearing as acetylated metabolite and 2-3% as glucuronide.
Dosage
Standard Dosage
Adults:
-
Malaria Treatment: Three tablets (Sulphadoxine 500mg / Pyrimethamine 25mg per tablet) as a single dose, usually administered after a 3-7 day course of quinine. Do not repeat for at least 7 days.
-
Malaria Prophylaxis: One tablet weekly starting 1-2 days before entering the endemic area, continuing during the stay, and for 4-6 weeks after departure. Alternatively, two tablets every two weeks using the same schedule.
Children:
-
Malaria Treatment: Dosage is weight-based and should be determined by a doctor. It can range from ½ tablet to 3 tablets as a single dose. The recommended dose, according to some sources, is 25 mg Sulfadoxine/1.25 mg Pyrimethamine per kg body weight.
-
Malaria Prophylaxis: Dosage is weight-based and should be determined by a doctor. It can range from ¼ to ¾ tablet weekly or ½ to 1½ tablets every two weeks.
Special Cases:
-
Elderly Patients: Dose adjustment may be necessary based on renal and hepatic function.
-
Patients with Renal Impairment: Dose reduction is recommended. Contraindicated in severe renal impairment.
-
Patients with Hepatic Dysfunction: Dose reduction is recommended. Contraindicated in severe hepatic impairment.
-
Patients with Comorbid Conditions: Caution is advised in patients with G6PD deficiency, blood dyscrasias, and folate deficiency. Avoid in those with a sulfonamide allergy.
Clinical Use Cases
Sulphadoxine/Pyrimethamine is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary role is in malaria prevention and treatment. For PCP prophylaxis, 1 tablet once or twice weekly may be considered if other options are unsuitable.
Dosage Adjustments
Dose modifications are necessary for renal and hepatic impairment. Genetic polymorphisms impacting drug metabolism should be considered.
Side Effects
Common Side Effects
Nausea, vomiting, diarrhea, headache, mild stomach pain, slight hair loss, anorexia, muscle weakness, depression, nervousness, ringing in the ears, insomnia, skin rash (including photosensitivity), itching, urticaria, dizziness.
Rare but Serious Side Effects
Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, aplastic anemia, thrombocytopenia, liver necrosis, hepatitis, jaundice, hepatomegaly, drug-induced eosinophilia, nephrotoxicity, severe cutaneous reactions, allergic reactions.
Long-Term Effects
Leukopenia, anaemia, and other blood dyscrasias with prolonged prophylaxis.
Adverse Drug Reactions (ADR)
Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), blood dyscrasias, fulminant hepatic necrosis, anaphylactoid reactions.
Contraindications
Hypersensitivity to sulfonamides or pyrimethamine, megaloblastic anemia due to folate deficiency, severe renal or hepatic impairment, blood dyscrasias, pregnancy at term, infants <2 months of age, breastfeeding (unless benefits outweigh the risks and no alternatives are available).
Drug Interactions
Antifolate drugs (e.g., methotrexate, trimethoprim, trimethoprim-sulfamethoxazole), other sulfonamides, chloroquine, didanosine, zidovudine, drugs with hepatic or haematological toxicity. High doses (>5 mg) of folic acid can reduce the efficacy of Sulphadoxine/Pyrimethamine. Many other drug interactions exist; consult a comprehensive drug interaction database.
Pregnancy and Breastfeeding
Pregnancy: FDA Pregnancy Category C. Contraindicated during the first trimester due to teratogenic potential. Can be used for intermittent preventive treatment during the second and third trimesters if benefits outweigh risks.
Breastfeeding: Pyrimethamine and sulfonamides are excreted in breast milk, posing a risk of kernicterus and hyperbilirubinemia in newborns, particularly premature infants or those with G6PD deficiency. Generally contraindicated, except when the benefits outweigh risks, such as when preventing malaria in breastfeeding mothers.
Drug Profile Summary
- Mechanism of Action: Inhibits dihydropteroate synthase, disrupting folic acid synthesis in the malaria parasite. Synergistic effect with pyrimethamine.
- Side Effects: Nausea, vomiting, diarrhea, headache, skin rash, serious skin reactions (rare).
- Contraindications: Sulfonamide hypersensitivity, folate deficiency, severe renal/hepatic impairment, first trimester of pregnancy.
- Drug Interactions: Antifolates, other sulfonamides, numerous other drugs (consult database).
- Pregnancy & Breastfeeding: Contraindicated in the first trimester and during breastfeeding (unless benefits outweigh risks).
- Dosage: Adults: 3 tablets single dose for treatment. 1 tablet weekly for prophylaxis. Pediatric doses are weight-based.
- Monitoring Parameters: Complete blood counts, liver function tests, urine analysis for crystalluria (long-term use).
Popular Combinations
Sulphadoxine/Pyrimethamine is commonly combined with artesunate for the treatment of uncomplicated malaria.
Precautions
Screen for allergies to sulfonamides, G6PD deficiency, renal/hepatic impairment. Avoid concomitant use of antifolates and high-dose folic acid. Ensure adequate hydration to prevent crystalluria. Discontinue at the first sign of skin rash. Caution in patients with pre-existing blood disorders.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Sulphadoxine/Pyrimethamine?
A: For adults, 3 tablets as a single dose for malaria treatment; 1 tablet weekly for prophylaxis. Pediatric dosing is weight-based.
Q2: What are the common side effects of Sulphadoxine/Pyrimethamine?
A: Common side effects include nausea, vomiting, diarrhea, headache, and skin rash.
Q3: When is Sulphadoxine/Pyrimethamine contraindicated?
A: Contraindicated in hypersensitivity to sulfa drugs, severe renal/hepatic disease, megaloblastic anemia due to folate deficiency, during the first trimester of pregnancy, and in infants under 2 months.
Q4: What are the serious side effects of Sulphadoxine/Pyrimethamine?
A: Stevens-Johnson syndrome, toxic epidermal necrolysis, blood dyscrasias, and severe hepatic reactions.
Q5: Can Sulphadoxine/Pyrimethamine be used during pregnancy?
A: Contraindicated during the first trimester. It can be used in the second and third trimesters for intermittent preventive treatment (IPTp) if benefits outweigh risks.
Q6: Can Sulphadoxine/Pyrimethamine be used during breastfeeding?
A: Generally contraindicated due to the risk of kernicterus in the newborn. Can be used if the benefits outweigh the risks and no safer alternatives are available.
Q7: What are the drug interactions with Sulphadoxine/Pyrimethamine?
A: Many interactions exist. Consult a comprehensive drug interaction database before co-prescribing. Avoid concomitant use of other antifolates, certain antimalarials, and high-dose folic acid.
Q8: How does Sulphadoxine/Pyrimethamine work?
A: Sulphadoxine inhibits dihydropteroate synthase, and Pyrimethamine inhibits dihydrofolate reductase, both crucial enzymes in the parasite’s folic acid synthesis pathway. The combined effect is synergistic and disrupts the parasite’s growth and replication.
Q9: What is the role of Sulphadoxine/Pyrimethamine in intermittent preventive treatment of malaria in pregnancy (IPTp)?
A: It is used in IPTp to protect pregnant women and their fetuses from the adverse effects of malaria, particularly during the second and third trimesters.
Q10: What precautions should be taken when prescribing Sulphadoxine/Pyrimethamine?
A: Screen for allergies, G6PD deficiency, and renal/hepatic impairment. Ensure adequate hydration. Discontinue at the first sign of skin rash. Monitor blood counts and liver function during prolonged use. Avoid concomitant use of other antifolates or high-dose folic acid.
