Pyrimethamine

Pyrimethamine is an antiparasitic drug.

Pyrimethamine is used in the treatment of Malaria, Toxoplasmosis and also used to treat Cystoisosporiasis (formerly Isosporiasis) in patients with HIV; Pneumocystis pneumonia in patients with HIV; Toxoplasma gondii encephalitis, primary prophylaxis/chronic maintenance therapy in patients with HIV.

Pyrimethamine is Almost completely absorbed from the gastrointestinal tract. Time to peak plasma concentration: 2-6 hours and Mainly distributed in the kidneys, lungs, liver, and spleen. Crosses placenta and enters breast milk. Volume of distribution: 2.9 L/kg. Plasma protein binding: Approx 80-90%. It is Metabolised in the liver and get excreted Via urine (16-32%). Elimination half-life: Approx 96 hours.

Pyrimethamine shows common side effects like Hives, Difficulty breathing, Swelling of your face, lips, tongue, or throat, Increased difficulty breathing, Chest pain, and Fever

Pyrimethamine is available in the form of tablet, Oral suspension and injectable solutions.

Pyrimethamine is available in India, Germany, Canada, Italy.

Pyrimethamine is an antiparasitic compound commonly used as an adjunct in the treatment of uncomplicated, chloroquine resistant, P. falciparum malaria. Pyrimethamine is a folic acid antagonist and the rationale for its therapeutic action is based on the differential requirement between host and parasite for nucleic acid precursors involved in growth. This activity is highly selective against plasmodia and Toxoplasma gondii. Pyrimethamine possesses blood schizonticidal and some tissue schizonticidal activity against malaria parasites of humans. However, the 4-amino-quinoline compounds are more effective against the erythrocytic schizonts. It does not destroy gametocytes, but arrests sporogony in the mosquito. The action of pyrimethamine against Toxoplasma gondii is greatly enhanced when used in conjunction with sulfonamides.

Pyrimethamine is available in the form of tablet, Oral suspension and injectable solutions.

Pyrimethamine is used in the treatment of Malaria, Toxoplasmosis and also used to treat Cystoisosporiasis (formerly Isosporiasis) in patients with HIV; Pneumocystis pneumonia in patients with HIV; Toxoplasma gondii encephalitis, primary prophylaxis/chronic maintenance therapy in patients with HIV.

Pyrimethamine inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver.

Pyrimethamine is approved for use in the following clinical indications

• Toxoplasmosis: Treatment of toxoplasmosis when used in combination with a sulfonamide.
• Although not approved there have been certain off label use documented for Pyrimethamine which includes:-

Cystoisosporiasis (formerly Isosporiasis) in patients with HIV; Pneumocystis pneumonia in patients with HIV; Toxoplasma gondii encephalitis, primary prophylaxis/chronic maintenance therapy in patients with HIV

• For Treatment of Acute Malaria: Pyrimethamine is NOT recommended alone in the treatment of acute malaria. Fast-acting schizonticides, such as chloroquine or quinine, are indicated for treatment of acute malaria. However, Pyrimethamine at a dosage of 25 mg daily for 2 days with a sulfonamide will initiate transmission control and suppression of Non-falciparum malaria. Pyrimethamine is only recommended for patients infected in areas where susceptible plasmodia exist. Should circumstances arise wherein Pyrimethamine must be used alone in semi-immune persons, the adult dosage for acute.

• Oral
• Toxoplasmosis
• Adult: In combination with a sulfonamide or another appropriate antibacterial: Initially, 100 mg for 1-2 days then 25-50 mg daily. Alternatively, 50-75 mg daily in combination with a sulfonamide and leucovorin calcium, for 1-3 weeks depending on patient response and tolerability. Dose may be reduced by 50% and continued for 4-5 weeks.
• Child: In combination with a sulfonamide or another appropriate antibacterial: 5-6 years Initially, 2mg/kg (Max: 50 mg), then 1mg/kg (Max: 25 mg) daily; >6 years Same as adult dose.
• For Chemoprophylaxis of Malaria:
• Adults and pediatric patients over 10 years — 25 mg (1 tablet) once weekly
• Children 4 through 10 years — 12.5 mg (1/2 tablet) once weekly
• Infants and children under 4 years — 6.25 mg (1/4 tablet) once weekly

Pyrimethamine is available in various strengths

• Tablets 25 and 50 mg, Suspension ( 25 mg/mL to 50 mg/mL) and injectable solutions (in combination)

Pyrimethamine is available in the form of tablet, Oral suspension and injectable solutions .

Dosage Adjustment for Pediatric Patients

• Cystoisosporiasis (formerly isosporiasis), HIV-exposed/-infected: Alternative therapy to sulfamethoxazole/trimethoprim.

Treatment :

Infants and Children: Oral: 1 mg/kg/day once daily in combination with leucovorin for 14 days; maximum daily dose: 25 mg/day .

Adolescents: Oral: 50 to 75 mg once daily in combination with leucovorin.

Chronic maintenance (secondary prophylaxis):

Infants and Children: Oral: 1 mg/kg/day once daily in combination with leucovorin; maximum daily dose: 25 mg/day.

Adolescents: Oral: 25 mg once daily in combination with leucovorin.

• Pneumocystis jirovecii pneumonia (PCP), HIV-exposed/-infected; primary prophylaxis or chronic maintenance (secondary prophylaxis): Alternative therapy :

Adolescents: Oral:

In combination with dapsone and leucovorin: 50 to 75 mg once weekly (dose depends on dapsone dose).

In combination with atovaquone and leucovorin: 25 mg once daily.

• Toxoplasmosis, acquired infection (including encephalitis); treatment:

HIV-exposed/-infected:

Infants and Children: Oral: 2 mg/kg/day (maximum dose: 50 mg/dose) once daily for 3 days followed by 1 mg/kg/day once daily (maximum dose: 25 mg/dose) in combination with leucovorin and either sulfadiazine or clindamycin; treat for at least 6 weeks; consider longer duration if clinical or radiologic disease is extensive or incomplete response; follow with chronic suppressive therapy in patients experiencing encephalitis .

Adolescents: Oral: Encephalitis: 200 mg once as a single dose, followed by weight-based daily dosing; treat for at least 6 weeks :

Weight <60 kg: 50 mg once daily.

Weight ≥60 kg: 75 mg once daily.

Non-HIV-exposed/-infected (Red Book [AAP 2018]):

Note: Use in combination with leucovorin and either sulfadiazine or clindamycin.

Infants, Children, and Adolescents:

<60 kg: Oral: Initial: 2 mg/kg/day in divided doses twice daily for 2 days (maximum dose: Chorioretinitis: 25 mg/dose; severe or CNS disease: 50 mg/dose); followed by 1 mg/kg/day once daily (maximum dose: Chorioretinitis: 25 mg/dose; severe or CNS disease: 50 mg/dose). Continue therapy for 1 to 2 weeks after symptom retablet , for a total therapy of 4 to 6 weeks.

≥60 kg: Oral: Initial: 2 mg/kg/day in divided doses twice daily for 2 days (maximum dose: Chorioretinitis: 25 mg/dose; severe or CNS disease: 50 mg/dose); followed by 1 mg/kg/day once daily (maximum dose: Chorioretinitis: 25 mg/dose; severe or CNS disease: 75 mg/dose). Continue therapy for 1 to 2 weeks after symptom retablet , for a total therapy of 4 to 6 weeks.

• Toxoplasmosis, congenital infection (independent of HIV status); treatment: In combination with sulfadiazine and leucovorin:

Infants: Oral: Initial: 2 mg/kg/day once daily or in 2 divided doses for 2 days, then 1 mg/kg/day once daily for 2 to 6 months, then 1 mg/kg/dose 3 times weekly (eg, Monday, Wednesday, Friday); maximum dose: 25 mg/dose; total treatment duration: 12 months

• Toxoplasmosis, prophylaxis, in hematopoietic cell transplantation recipients :

Infants and Children: Oral: 1 mg/kg/day once daily with clindamycin and leucovorin; maximum dose: 75 mg/dose. Start after engraftment and administer as long as the patient remains on immunosuppressive therapy.

Adolescents: Oral: 25 to 75 mg once daily with clindamycin and leucovorin. Start after engraftment and administer as long as the patient remains on immunosuppressive therapy.

• Toxoplasmosis, prophylaxis, in HIV-exposed/-infected patients:

Primary prophylaxis: Alternative therapy to sulfamethoxazole/trimethoprim:

Infants and Children : Oral:

In combination with dapsone and oral leucovorin: 1 mg/kg/day once daily; maximum dose: 25 mg/dose.

In combination with atovaquone and oral leucovorin: Infants and Children 4 to 24 months: 1 mg/kg/day or 15 mg/m2/day once daily; maximum dose: 25 mg/dose.

Adolescents : Oral:

In combination with dapsone and oral leucovorin: 50 mg or 75 mg once weekly.

In combination with atovaquone and oral leucovorin: 25 mg once daily.

Secondary prophylaxis/suppressive therapy:

Infants and Children: Oral: 1 mg/kg/day or 15 mg/m2/day once daily (maximum dose: 25 mg/dose) with leucovorin and sulfadiazine, clindamycin, or atovaquone.

Adolescents : Oral:

In combination with sulfadiazine or clindamycin: 25 to 50 mg once daily plus leucovorin.

In combination with atovaquone: 25 mg once daily plus leucovorin.

Hypersensitivity.

Megaloblastic anemia secondary to folate deficiency.

1^st trimester of pregnancy.

Lactation.

Concerns related to adverse effects:

• Hematologic: Megaloblastic anemia, leukopenia, thrombocytopenia, neutropenia, and pancytopenia have been reported; most commonly with high doses.

Disease-related concerns:

• Folate deficiency: Use caution in patients with possible folate deficiency (eg, malabsorption syndrome, alcoholism).

• G6PD deficiency: Use with caution in patients with possible G6PD deficiency.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment.

• Seizure disorders: Use with caution in patients with a history of seizure disorders.

Pregnancy Category C.

Pyrimethamine has been shown to be teratogenic in rats when given in oral doses 7 times the human dose for chemoprophylaxis of malaria or 2.5 times the human dose for treatment of toxoplasmosis. At these doses in rats, there was a significant increase in abnormalities such as cleft palate, brachygnathia, oligodactyly, and microphthalmia. Pyrimethamine has also been shown to produce terata such as meningocele in hamsters and cleft palate in miniature pigs when given in oral doses 170 and 5 times the human dose, respectively, for chemoprophylaxis of malaria or for treatment of toxoplasmosis.

• Common Adverse effects:-

Megaloblastic anemia, leucopenia, thrombocytopenia, pancytopenia; Crystalluria (with sulfonamides).

• Less Common Adverse effects:-

Nausea, vomiting, diarrhea, glossitis.

• Rare Adverse effects:-

Rash, abnormal skin pigmentation, dermatitis.

May cause convulsion with methotrexate in patient with CNS leukaemia, and seizures with antimalarial drugs. Further depression of folate metabolism with co-trimoxazole, proguanil, zidovudine, or cytostatic agents (e.g. methotrexate). Decreased absorption with antacids and kaolin. Increased risk of hepatotoxicity with lorazepam.

Potentially Fatal: May cause bone marrow aplasia with daunorubicin, cytosine arabinoside in patient with acute myeloid leukaemia.

The common side effects of Pyrimethamine include the following Hives, Difficulty breathing, Swelling of your face, lips, tongue, or throat, Increased difficulty breathing, Chest pain, and Fever

Symptoms: Severe and repeated vomiting, nausea, abdominal pain, convulsions, ataxia, tremor, and respiratory depression.

Management: Symptomatic and supportive treatment. Maintain the airways and perform gastric lavage. May administer diazepam to control convulsions; calcium folinate for possible folinate deficiency.

Pharmacodynamics

Pyrimethamine is an antiparasitic compound commonly used as an adjunct in the treatment of uncomplicated, chloroquine resistant, P. falciparum malaria. Pyrimethamine is a folic acid antagonist and the rationale for its therapeutic action is based on the differential requirement between host and parasite for nucleic acid precursors involved in growth. This activity is highly selective against plasmodia and Toxoplasma gondii. Pyrimethamine possesses blood schizonticidal and some tissue schizonticidal activity against malaria parasites of humans. However, the 4-amino-quinoline compounds are more effective against the erythrocytic schizonts. It does not destroy gametocytes, but arrests sporogony in the mosquito. The action of pyrimethamine against Toxoplasma gondii is greatly enhanced when used in conjunction with sulfonamides.

Pharmacokinetics

• Absorption: Almost completely absorbed from the gastrointestinal tract. Time to peak plasma concentration: 2-6 hours.
• Distribution: Mainly distributed in the kidneys, lungs, liver, and spleen. Crosses placenta and enters breast milk. Volume of distribution: 2.9 L/kg. Plasma protein binding: Approx 80-90%.
• Metabolism: Metabolised in the liver.
• Excretion: Via urine (16-32%). Elimination half-life: Approx 96 hours.

• https://www.uptodate.com/contents/topical-agents-and-dressings-for-local-burn-wound-care
• https://www.mims.com/india/drug/info/silver Pyrimethamine ?type=full
• https://go.drugbank.com/drugs/DB00359