Usage
- Medical Conditions: Pyrimethamine + Sulfamethoxazole is prescribed for the treatment and prophylaxis of malaria caused by Plasmodium falciparum, particularly in areas with chloroquine-resistant strains. It’s also indicated for toxoplasmosis, and as an alternative for Pneumocystis jirovecii pneumonia (PCP) prophylaxis when other options are not feasible.
- Pharmacological Classification: Antimalarial, Antiparasitic, Antibiotic (Sulfonamide)
- Mechanism of Action: Pyrimethamine inhibits dihydrofolate reductase, and sulfamethoxazole inhibits dihydropteroate synthase. These combined actions disrupt the folic acid synthesis pathway in susceptible organisms, leading to impaired DNA synthesis and ultimately, cell death.
Alternate Names
- Fansidar (brand name)
- S-Pyrimac (brand name)
- Swidar (brand name)
- Vitadar (brand name)
- MA163 (brand name)
- G-COSPE® (brand name)
How It Works
- Pharmacodynamics: Pyrimethamine and sulfamethoxazole act synergistically to inhibit folic acid synthesis. This results in the disruption of DNA synthesis and ultimately cell death in susceptible organisms like Plasmodium falciparum and Toxoplasma gondii.
- Pharmacokinetics:
- Absorption: Both drugs are well-absorbed orally.
- Metabolism: Pyrimethamine is metabolized to several metabolites.
- Elimination: Both drugs have long elimination half-lives (approximately 100 hours for pyrimethamine and 200 hours for sulfadoxine). Excretion is primarily renal.
- Mode of Action: Sequential blockade of folic acid synthesis pathway.
- Receptor Binding, Enzyme Inhibition or Neurotransmitter Modulation: Dihydrofolate reductase inhibition (Pyrimethamine) and dihydropteroate synthase inhibition (Sulfamethoxazole)
- Elimination Pathways: Primarily renal excretion.
Dosage
Standard Dosage
Adults:
- Malaria Treatment: 2-3 tablets (equivalent to 50-75 mg pyrimethamine and 1000-1500 mg sulfadoxine) as a single dose, often following a course of quinine.
- Malaria Prophylaxis: 1 tablet weekly or 2 tablets every two weeks, starting 1-2 days before travel to an endemic area and continuing for 4-6 weeks after return.
- Intermittent Preventive Treatment of Malaria in Pregnancy (IPTp): 3 tablets as a single dose at monthly intervals during the second and third trimesters (at least one month apart), ideally under directly observed therapy (DOT).
Children:
- Malaria Treatment: Dosage based on weight (see source material for specific recommendations) and may be preceded by a course of quinine.
- Malaria Prophylaxis: Dosage based on weight (see source material for specific recommendations).
- Perennial Malaria Chemoprevention: Dosage based on weight and should be administered at least monthly to children up to 24 months old in eligible areas. For children under 5 kg an alternate formulation needs to be used. Children above 5 kg may receive half a tablet.
- Children less than 2 months: Contraindicated.
Special Cases:
- Elderly Patients: Use with caution; dose adjustment may be necessary due to potential reduced hepatic and renal function.
- Patients with Renal Impairment: Use with caution; dose adjustment may be necessary. Contraindicated for repeated prophylactic use in patients with renal failure.
- Patients with Hepatic Dysfunction: Use with caution; dose adjustment may be necessary. Contraindicated for repeated prophylactic use in patients with hepatic failure.
- Patients with Comorbid Conditions: Monitor carefully for adverse effects, particularly in patients with HIV infection taking co-trimoxazole, G6PD deficiency, blood disorders, or those with pre-existing folate deficiency. Do not use in combination with co-trimoxazole.
Clinical Use Cases
- Intubation: Not specifically indicated.
- Surgical Procedures: Not specifically indicated for surgical prophylaxis.
- Mechanical Ventilation: Not specifically indicated.
- Intensive Care Unit (ICU) Use: May be used in the ICU setting for treatment or prophylaxis of PCP if other options are unsuitable, but this is not a common indication.
- Emergency Situations: Not typically used in most emergency situations.
Dosage Adjustments:
- Renal/Hepatic Dysfunction: Dose adjustment may be required; contraindicated for repeated prophylactic use in patients with renal or hepatic failure.
- Metabolic Disorders: Use cautiously in patients with G6PD deficiency due to the risk of hemolytic anemia.
- Genetic Polymorphisms: No specific adjustments outlined in the provided sources.
Side Effects
Common Side Effects:
- Nausea, vomiting, diarrhea
- Headache
- Mild hair loss
- Muscle weakness
- Mild stomach pain, feeling of fullness
- Itching, skin rash
- Depression, nervousness
- Ringing in the ears
- Sleep problems (insomnia)
Rare but Serious Side Effects:
- Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
- Bone marrow suppression (anemia, leukopenia, thrombocytopenia, agranulocytosis, aplastic anemia)
- Hemolytic anemia (especially in patients with G6PD deficiency)
- Liver injury (hepatitis, jaundice)
- Hypersensitivity reactions (anaphylaxis)
- Megaloblastic anemia due to folate deficiency
- Hyperkalemia
- Pulmonary toxicity (cough, shortness of breath)
Long-Term Effects:
- Potential for folate deficiency with prolonged use.
- Possible development of drug resistance with prolonged prophylactic use.
Adverse Drug Reactions (ADR):
- Any signs of severe skin reactions (rash, blisters, peeling skin)
- Signs of blood disorders (unusual bruising or bleeding, fatigue, pallor, fever, sore throat)
- Signs of liver damage (yellowing of skin or eyes, dark urine, right upper quadrant pain)
- Signs of hypersensitivity (swelling of face, lips, tongue, difficulty breathing)
Contraindications
- Hypersensitivity to pyrimethamine, sulfadoxine, or any sulfonamides.
- Megaloblastic anemia due to folate deficiency.
- Infants < 2 months of age.
- Pregnancy at term (for prophylaxis).
- Breastfeeding women (for prophylaxis).
- Acute porphyria.
- Repeated/prolonged use in patients with renal or hepatic failure.
Drug Interactions
- Antifolate Drugs: (e.g., trimethoprim, methotrexate, sulfonamides): Increased risk of bone marrow suppression.
- Drugs that Lower Folate Levels: (e.g., phenytoin): Increased risk of megaloblastic anemia.
- Myelosuppressive Drugs: (e.g., zidovudine, proguanil, chemotherapy agents): Increased risk of bone marrow suppression.
- Co-trimoxazole: Increased risk of adverse reactions.
- Chloroquine: Potential increase in incidence and severity of adverse reactions.
- Digoxin: Increased plasma digoxin levels, especially in elderly patients.
- Lorazepam: Mild hepatotoxicity reported with concomitant use.
- Other potential interactions: Penicillamine, dofetilide.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C. Contraindicated during the first trimester. May be used in the second and third trimesters for IPTp if benefits outweigh risks.
- Fetal Risks: Teratogenic effects observed in animal studies. Potential for neural tube defects in the first trimester.
- Breastfeeding: Not recommended for prophylactic use. Limited data suggests compatibility with breastfeeding for treatment, but infants should not receive any other antifolate agents.
Drug Profile Summary
- Mechanism of Action: Inhibits folic acid synthesis by blocking dihydrofolate reductase (pyrimethamine) and dihydropteroate synthase (sulfadoxine).
- Side Effects: Nausea, vomiting, diarrhea, headache, skin rash, bone marrow suppression, severe skin reactions (rare).
- Contraindications: Hypersensitivity, megaloblastic anemia due to folate deficiency, infants <2 months, first trimester of pregnancy, renal/hepatic failure (for prolonged use).
- Drug Interactions: Antifolates, myelosuppressive drugs, co-trimoxazole, chloroquine, digoxin.
- Pregnancy & Breastfeeding: Contraindicated in first trimester, use with caution in second and third trimesters for IPTp; not recommended for prophylactic use during breastfeeding.
- Dosage: Varies depending on indication and patient factors; see detailed dosage section.
- Monitoring Parameters: Complete blood counts, liver function tests, renal function tests (for long-term use), urinalysis (crystalluria).
Popular Combinations
- Quinine: Often given before pyrimethamine/sulfadoxine for malaria treatment.
- Other antimalarials: May be combined depending on the region-specific malaria resistance patterns.
Precautions
- General Precautions: Assess for allergies, pre-existing blood disorders, liver/kidney function, G6PD deficiency, and folate status before administering.
- Specific Populations:
- Pregnant Women: Contraindicated in the first trimester; use cautiously in the second and third trimesters only for IPTp if benefits outweigh risks. Supplementation with folic acid is crucial.
- Breastfeeding Mothers: Avoid use for prophylaxis. Exercise caution if using for treatment, and monitor the infant for side effects.
- Children & Elderly: Adjust dosage accordingly; contraindicated in infants < 2 months.
- Lifestyle Considerations: No specific lifestyle restrictions mentioned in sources.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Pyrimethamine + Sulfamethoxazole?
A: Dosage varies according to indication and patient factors (age, weight, renal/hepatic function). See detailed dosage guidelines above.
Q2: What are the most common side effects?
A: Nausea, vomiting, diarrhea, headache, skin rash are common side effects.
A: Severe skin reactions (Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis), bone marrow suppression, and hemolytic anemia are serious side effects.
Q4: Can this medication be used during pregnancy?
A: Contraindicated in the first trimester. May be used cautiously during the second and third trimesters for intermittent preventive treatment of malaria (IPTp) if the benefits outweigh the risks, with folic acid supplementation.
Q5: What are the contraindications to using Pyrimethamine + Sulfamethoxazole?
A: Hypersensitivity, megaloblastic anemia due to folate deficiency, infants under 2 months, pregnancy at term (for prophylaxis), kidney/liver failure (for repeated/long-term use).
Q6: What are the key drug interactions to be aware of?
A: Interactions with other antifolate drugs (e.g., trimethoprim, methotrexate), myelosuppressive medications, co-trimoxazole, chloroquine, and digoxin.
Q7: How is Pyrimethamine + Sulfamethoxazole eliminated from the body?
A: Primarily through renal excretion.
Q8: How should patients with renal impairment be managed?
A: Use with caution and consider dose adjustment. Repeated prophylactic use is contraindicated in patients with renal failure.
Q9: Is this medication effective against all types of malaria?
A: Primarily indicated for malaria caused by Plasmodium falciparum, particularly chloroquine-resistant strains. It may not be effective against other malaria species.
