Intertrim LA+ 100 mL

Indications

• Treatment of malaria caused by Plasmodium falciparum
• Prevention of malaria in individuals traveling to endemic areas

Dosage

Children: Refer to BNF for Children for specific dosing information.

Adults: Refer to BNF for specific dosing information.

Mechanism of action

Sulfadoxine acts as an antimetabolite by competitively inhibiting the enzyme dihydropteroate synthase, which is crucial for the synthesis of folic acid from para-aminobenzoic acid (PABA). This inhibition disrupts the folic acid production necessary for DNA synthesis and cellular growth in the Plasmodium species, particularly P. falciparum, thereby impairing its ability to reproduce.

Pharmacodynamics

Sulfadoxine's inhibition of dihydropteroate synthetase leads to a decrease in folic acid levels within the parasite. Folic acid is essential for the synthesis, repair, and methylation of DNA, and its deficiency hampers the growth and replication of Plasmodium falciparum, thereby aiding in the treatment of malaria.

Pharmacokinetics

Sulfadoxine is well-absorbed after oral administration, with peak plasma concentrations typically reached within 4 to 6 hours. It has a long half-life, allowing for once-daily dosing in many cases. The drug is metabolized in the liver and excreted primarily via the kidneys. Its pharmacokinetic profile supports its use in combination therapies for malaria, as it maintains therapeutic levels over extended periods.

Contra-indications

• Hypersensitivity to sulfadoxine or other sulfonamides
• Severe liver or kidney impairment
• Pregnancy at term
• Infants under 2 months of age

Adverse effects

• Nausea
• Vomiting
• Rash
• Fever
• Anemia
• Leukopenia
• Thrombocytopenia
• Hepatotoxicity
• Stevens-Johnson syndrome

Interactions

• May enhance the effects of anticoagulants such as warfarin
• May interact with methotrexate, increasing its toxicity
• May reduce the effectiveness of certain oral contraceptives

Precautions

• Monitor for signs of hypersensitivity reactions
• Use cautiously in patients with G6PD deficiency
• Assess renal function prior to and during therapy

Pregnancy

Use is contraindicated at term due to the risk of kernicterus in the neonate. Caution is advised during the first and second trimesters.

Breast-feeding

Sulfadoxine is excreted in breast milk; caution is advised when administering to breastfeeding mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Sulfadoxine 500 mg tablets
• Sulfadoxine/pyrimethamine combination tablets

Indications

• Bacterial infections
• Urinary tract infections
• Respiratory tract infections
• Prophylaxis of recurrent urinary tract infections

Dosage

Children: For children aged 6 weeks to 5 months: 4 mg/kg twice daily (max. 200 mg). For children 6 months to 5 years: 4 mg/kg twice daily (max. 200 mg). For children 6–11 years: 4 mg/kg twice daily (max. 200 mg). For children

Adults: 200 mg twice daily.

Mechanism of action

Trimethoprim is a reversible inhibitor of dihydrofolate reductase, an enzyme that catalyzes the formation of tetrahydrofolic acid from dihydrofolic acid. By inhibiting this enzyme, trimethoprim disrupts the biosynthesis of nucleic acids and proteins in bacteria, leading to their growth inhibition. The drug has a significantly higher affinity for bacterial dihydrofolate reductase compared to the mammalian enzyme, ensuring selective antibacterial activity.

Pharmacodynamics

Trimethoprim exerts its antimicrobial effects by disrupting bacterial nucleic acid synthesis. It is effective against various gram-negative bacteria and some coagulase-negative Staphylococcus species. Resistance can develop through mechanisms such as alterations to the bacterial cell wall or overproduction of the target enzyme. Monitoring for potential blood disorders is important during therapy, as rare adverse effects can occur.

Pharmacokinetics

Trimethoprim is well absorbed from the gastrointestinal tract and reaches peak plasma concentrations within 1-4 hours post-administration. It has a volume of distribution that suggests extensive tissue penetration, including into the lungs and kidneys, and is primarily excreted unchanged in the urine. The elimination half-life is approximately 8-10 hours, and dosing adjustments may be necessary in cases of renal impairment.

Contra-indications

• Severe renal impairment
• Known hypersensitivity to trimethoprim or any component of the formulation

Adverse effects

• Diarrhoea
• Nausea
• Headache
• Dizziness
• Fatigue
• Skin reactions
• Vomiting
• Anxiety
• Agranulocytosis
• Eosinophilia
• Photosensitivity reactions
• Thrombocytopenia
• Leukopenia
• Pseudomembranous colitis

Interactions

• Increases exposure to pramipexole
• Increases exposure to treprostinil
• Increases exposure to dopaminergic receptor agonists
• Increases concentration of antiepileptics
• Increases concentration of fosphenytoin
• Increases concentration of phenytoin
• Increases risk of haematological toxicity with azathioprine in renal transplant patients
• Increases concentration of digoxin
• Increases exposure to repaglinide

Precautions

• Caution in patients with renal impairment
• Caution in elderly patients (75 years and over)
• Monitor for signs of blood disorders such as sore throat, fever, and pallor
• Consider local antimicrobial susceptibility patterns before use

Pregnancy

Manufacturer advises avoidance due to potential fetal developmental toxicity observed in animal studies.

Breast-feeding

Manufacturer advises avoidance as trimethoprim is present in milk in animal studies.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets
• Oral suspension
• Injection solution

Mechanism of action

Sulfadoxine is a sulfa drug, often used in combination with pyrimethamine to treat malaria. This medicine may also be used to prevent malaria in people who are living in, or will be traveling to, an area where there is a chance of getting malaria. Sulfadoxine targets Plasmodium dihydropteroate synthase and dihydrofolate reductase. Sulfa drugs or Sulfonamides are antimetabolites. They compete with para-aminobenzoic acid (PABA) for incorporation into folic acid. The action of sulfonamides exploits the difference between mammal cells and other kinds of cells in their folic acid metabolism. All cells require folic acid for growth. Folic acid (as a vitamin) diffuses or is transported into human cells. However, folic acid cannot cross bacterial (and certain protozoan) cell walls by diffusion or active transport. For this reason bacteria must synthesize folic acid from p-aminobenzoic acid.

Pharmacodynamics

Sulfadoxine helps inhibit the enzyme dihydropteroate synthetase which is an enzyme necessary in the conversion of PABA to folic acid. As folic acid is vital to the synthesis, repair, and methylation of DNA which is vital to cell growth in Plasmodium falciparum. With this vital nutrient lacking, the parasite has difficulty in reproducing.

Mechanism of action

Trimethoprim is a reversible inhibitor of dihydrofolate reductase, one of the principal enzymes catalyzing the formation of tetrahydrofolic acid (THF) from dihydrofolic acid (DHF). Tetrahydrofolic acid is necessary for the biosynthesis of bacterial nucleic acids and proteins and ultimately for continued bacterial survival - inhibiting its synthesis, then, results in bactericidal activity. Trimethoprim binds with a much stronger affinity to bacterial dihydrofolate reductase as compared to its mammalian counterpart, allowing trimethoprim to selectively interfere with bacterial biosynthetic processes. Trimethoprim is often given in combination with sulfamethoxazole, which inhibits the preceding step in bacterial protein synthesis - given together, sulfamethoxazole and trimethoprim inhibit two consecutive steps in the biosynthesis of bacterial nucleic acids and proteins. As a monotherapy trimethoprim is considered bacteriostatic, but in combination with sulfamethoxazole is thought to exert bactericidal activity. Trimethoprim is a bacteriostatic lipophilic weak base structurally related to pyrimethamine. It binds to and reversibly inhibits the bacterial enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with bacterial nucleic acid and protein production. Bacterial dihydrofolate reductase is approximately 50,000 to 60,000 times more tightly bound by trimethoprim than is the corresponding mammalian enzyme. To determine the incidence & severity of hyperkalemia during trimethoprim therapy, 30 consecutive patients with acquired immunodeficiency syndrome receiving high-dose (20 mg/kg/day) trimethoprim were studied; in addition, the mechanism of trimethoprim-induced hyperkalemia was investigated in rats. Trimethoprim increased serum potassium concn by 0.6 mmol/l despite normal adrenocortical function & glomerular filtration rate. Serum potassium levels >5 mmol/l were observed during trimethoprim treatment in 15 of 30 patients. In rats, iv trimethoprim inhibited renal potassium excretion by 40% & increased sodium excretion by 46%. It was concluded that trimethoprim blocks apical membrane sodium channels in the mammalian distal nephron. As a consequence, the transepithelial voltage is reduced & potassium secretion is inhibited. Decreased renal potassium excretion secondary to these direct effects on kidney tubules leads to hyperkalemia in a substantial number of patients being treated with trimethoprim-containing drugs.

Pharmacodynamics

Trimethoprim exerts its antimicrobial effects by inhibiting an essential step in the synthesis of bacterial nucleic acids and proteins. It has shown activity against several species of gram-negative bacteria, as well as coagulase-negative _Staphylococcus_ species. Resistance to trimethoprim may arise via a variety of mechanisms, including alterations to the bacterial cell wall, overproduction of dihydrofolate reductase, or production of resistant dihydrofolate reductase. Rarely, trimethoprim can precipitate the development of blood disorders (e.g. thrombocytopenia, leukopenia, etc.) which may be preceded by symptoms such as sore throat, fever, pallor, and or purpura - patients should be monitored closely for the development of these symptoms throught the course of therapy. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.