Pharm 101: Trimethoprim

Class

Antifolate antibiotic

Pharmacodynamics

• Blocks step in folate synthesis
• Selectively inhibits bacterial dihydrofolic acid reductaste that converts dihydrofolic acid to tetrahydrofolic acid, a step leading to synthesis of purines and ultimately DNA
  • Hence inhibits DNA synthesis
  • Much less efficient in inhibiting mammalian DHFR
• Bacterostatic on its own
• Mechanisms of resistance to trimethoprim:
  • Reduced cell permeability
  • Increased production of enzyme DHF reductase
  • Alteration in DHF reductase with reducing binding

Trimethoprim-sulfamethoxazole combination

• Trimethoprim in combination with sulphonamides becomes bactericidal (synergistic effect), due to blockade of sequential steps in folate synthesis:
  • Sulphonamides inhibit dihydropteroate synthase, which catalyses PABA to DHFA (step before trimethoprim)

Pharmacokinetics

• PO administration
• Weak base
  • Concentrations in prostatic fluid and vaginal fluid (more acidic than plasma)
• Well absorbed and well distributed including to CSF
• 45% protein bound
• 60% excreted in urine within 24 hours

Antimicrobial activity

• Clinical uses of trimethoprim:
  • UTI
• See Pharm 101: Trimethoprim-Sulfamethoxazole for other clinical uses in combination with sulphonamides

Adverse effects

• Haematological:
  • Megaloblastic anaemia
  • Leukopenia
  • Granulocytopaenia
• Renal:
  • Mild elevation of serum creatinine without impairment of GFR (nontoxic)

Further reading

• Buttner R. Pharm 101: Trimethoprim-Sulfamethoxazole. LITFL

References

• Katzung BG. Basic and Clinical Pharmacology. 14e. 2018: 836-837, 840