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
Adverse effects
  • Haematological:
    • Megaloblastic anaemia
    • Leukopenia
    • Granulocytopaenia
  • Renal:
    • Mild elevation of serum creatinine without impairment of GFR (nontoxic)
Further reading
References
Pharm 101 700

Pharmacology 101

Top 200 drugs

MBBS CCPU (RCE, Biliary, DVT, E-FAST, AAA) Rob is an Emergency Medicine Advanced Trainee based in Melbourne, Australia. He has special interests in medical education, ECG interpretation, and the use of diagnostic and procedural ultrasound in the undifferentiated and unwell patient.

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