Usage
- This combination drug is primarily prescribed for the treatment of uncomplicated Plasmodium falciparum malaria. It is also used as part of combination therapy to mitigate the development of drug resistance in malaria parasites. It should be followed by primaquine to prevent relapse in P. vivax and P. ovale malaria.
- Pharmacological Classification: Antimalarial.
- Mechanism of Action: This combination targets different stages of the malaria parasite’s life cycle. Artesunate, an artemisinin derivative, generates free radicals that damage the parasite, especially during the blood stage. Pyrimethamine inhibits dihydrofolate reductase (DHFR), disrupting folic acid synthesis needed for parasite DNA replication. Sulfadoxine, a sulfonamide antibiotic, inhibits dihydropteroate synthetase (DHPS), another enzyme crucial for the parasite’s folic acid production.
Alternate Names
- Artesunate plus sulfadoxine-pyrimethamine (AS+SP)
- SP-ACT (Sulfadoxine-Pyrimethamine with Artesunate)
- Fansidar (for the sulfadoxine-pyrimethamine component)
How It Works
- Pharmacodynamics: The combined action of the three drugs disrupts multiple metabolic pathways vital for the Plasmodium parasite’s survival and reproduction, leading to its eradication.
- Pharmacokinetics:
- Artesunate: Rapidly absorbed and metabolized to its active metabolite, dihydroartemisinin (DHA). Eliminated primarily via hepatic metabolism.
- Pyrimethamine: Well-absorbed orally. Metabolized in the liver and excreted through the kidneys.
- Sulfadoxine: Absorbed well orally and excreted mainly through the kidneys.
- Mode of Action: See “Mechanism of Action” in the Usage section above.
- Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Pyrimethamine inhibits DHFR. Sulfadoxine inhibits DHPS.
- Elimination Pathways: Artesunate is metabolized and eliminated by the liver. Pyrimethamine is metabolized in the liver and eliminated through the kidneys. Sulfadoxine is primarily eliminated through the kidneys.
Dosage
Standard Dosage
Adults: The standard dosage is based on body weight: Artesunate 4 mg/kg daily for 3 days, and a single dose of Sulfadoxine 25 mg/kg + Pyrimethamine 1.25 mg/kg (administered with the first dose of Artesunate). For patients ≥ 50 kg, the blister pack with 6 tabs AS 100 mg and 3 tabs SP 500/25 mg may be used.
Children: Dosage is weight-based. Please see detailed weight-based dosing charts in source [3]. Pediatric safety considerations include careful calculation of the dose based on weight to avoid toxicity.
Special Cases:
- Elderly Patients: Use with caution and monitor for adverse events. Dosage adjustment may be necessary based on renal and hepatic function.
- Patients with Renal Impairment: Use with caution. Dosage adjustment may be necessary.
- Patients with Hepatic Dysfunction: Use with caution. Dosage adjustment may be necessary.
- Patients with Comorbid Conditions: Caution is advised in patients with epilepsy, asthma, blood disorders, depression, schizophrenia, severe anxiety, G6PD deficiency, colitis and porphyria.
Clinical Use Cases
- The combination is not indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. It is specifically intended for the treatment of uncomplicated P. falciparum malaria.
Dosage Adjustments
- Dose modifications are necessary for renal/hepatic impairment based on clinical judgment.
Side Effects
Common Side Effects:
Nausea, vomiting, dizziness, abdominal pain, headache, diarrhea, fatigue, loss of appetite, skin rash.
Rare but Serious Side Effects:
Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), blood disorders (agranulocytosis, aplastic anemia, thrombocytopenia), liver damage (hepatitis, liver necrosis), kidney problems (nephrosis), seizures, mental changes.
Long-Term Effects:
Data on long-term effects are limited.
Adverse Drug Reactions (ADR):
Any of the rare but serious side effects listed above require urgent medical attention.
Contraindications
- Hypersensitivity to sulfonamides or pyrimethamine.
- Megaloblastic anemia due to folate deficiency.
- Severe hepatic or renal impairment (except when no alternative treatment is available).
- First trimester of pregnancy.
- Infants < 2 months of age.
Drug Interactions
- Anticonvulsants (carbamazepine, phenytoin): May decrease antimalarial activity.
- Antiretrovirals (ritonavir, nevirapine): May alter drug metabolism.
- Antibiotics (rifampin): May reduce efficacy.
- Antimalarials (chloroquine, mefloquine): Avoid co-administration.
- Antimetabolites (methotrexate, trimethoprim): Increased risk of bone marrow suppression.
- Warfarin and other blood thinners.
- Diuretics (e.g., furosemide).
- Co-trimoxazole: Do not co-administer.
- Folic acid: Do not administer on the same day as SP or within 2 weeks thereafter.
Pregnancy and Breastfeeding
- Pregnancy: Contraindicated during the first trimester. Use with caution during the second and third trimesters only if the benefit outweighs the risk.
- Breastfeeding: Contraindicated. The drug passes into breast milk and can cause adverse effects in infants.
Drug Profile Summary
- Mechanism of Action: See “Mechanism of Action” under Usage.
- Side Effects: See “Side Effects” section.
- Contraindications: See “Contraindications” section.
- Drug Interactions: See “Drug Interactions” section.
- Pregnancy & Breastfeeding: See “Pregnancy and Breastfeeding” section.
- Dosage: See “Dosage” section.
- Monitoring Parameters: Monitor for adverse events, including skin reactions, blood disorders, and liver or kidney dysfunction. Monitor hemoglobin levels for 4 weeks after artesunate therapy.
Popular Combinations
Artesunate + Sulfadoxine-Pyrimethamine is itself a popular and WHO-recommended combination.
Precautions
- Pre-screening for allergies, G6PD deficiency, and organ dysfunction.
- Caution in patients with pre-existing medical conditions (as listed in contraindications and drug interactions).
- Avoid alcohol consumption.
- May impair ability to drive or operate machinery.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Artesunate + Pyrimethamine + Sulphadoxine?
A: See “Dosage” section.
Q2: What are the common side effects?
A: The common side effects include nausea, vomiting, dizziness, abdominal pain, headache, diarrhea, and fatigue.
Q3: Can this drug be used in pregnant or breastfeeding women?
A: Contraindicated in the first trimester of pregnancy and during breastfeeding. Use with caution during the second and third trimesters only if the benefit outweighs the risk.
Q4: What are the serious side effects I should watch out for?
A: Severe skin reactions, blood disorders, liver damage, kidney problems, and seizures are rare but serious side effects.
Q5: What are the contraindications to using this combination?
A: Known hypersensitivity to sulfonamides or pyrimethamine, megaloblastic anemia due to folate deficiency, severe liver or kidney disease, first trimester of pregnancy, and infants under 2 months of age.
Q6: Are there any drug interactions I should be aware of?
A: Yes, it can interact with anticonvulsants, antiretrovirals, antibiotics, other antimalarials, antimetabolites, and warfarin, amongst others. See the “Drug Interactions” section for a full list.
Q7: Can this drug be used for all types of malaria?
A: Primarily indicated for uncomplicated P. falciparum malaria. It should be followed by primaquine to prevent relapse in P. vivax and P. ovale malaria.
Q8: What should I do if a patient misses a dose?
A: Take the missed dose as soon as you remember, but never double the dose.
Q9: Should any specific monitoring parameters be considered?
A: Yes, patients should be monitored for adverse events, particularly dermatological, hematological, and hepatic or renal reactions. Hemoglobin should be monitored for 4 weeks following artesunate treatment.
Q10: What is the mechanism of action of this drug combination?
A: The combination targets multiple pathways in the malaria parasite. Artesunate damages the parasite through free radical formation. Pyrimethamine inhibits DHFR, affecting DNA synthesis. Sulfadoxine inhibits DHPS, further disrupting folate synthesis.
