Anti-Metabolites

ANTI-METABOLITES


ANTI-METABOLITES

  • MOA: Interferes with cellular metabolism.
  • Drugs: Sulfonamides, trimethoprim, pyrimethamine, proguanil & methotrexate.

Important drug details:

1. Sulfonamides:

  • Bacteriostatic agents.

MOA:

  • Acts by inhibiting folate synthase competitively.
  • Ineffective in presence of pus –
  • Due to excessive PABA levels.

Metabolism: Hepatic by acetylation.

Classification:

  • For systemic use as oral agents:
    • Short acting: Sulfisoxazole, sulfamethiazole, sulfacytine.
    • Intermediate acting: Sulfamethoxazole, sulfadiazine.
    • Long acting: Sulfadoxine
  • For use in GIT:
    • Sulfasalazine, olsalazine
  • For topical use:
    • Sulfacetamide, silver sulfadiazine, mafenide

Clinical uses:

  • For ocular infections – Sulfacetamide.
  • In burn patients as topical agents – Mafenide & silver sulfadiazine
  • In nocardiosis – Sulfadiazine.
  • For urinary tract infections – Sulfisoxazole.
  • For ulcerative colitis treatment – Sulfasalazine & olsalazine.
  • For malaria, toxoplasmosis treatment & Pneumocystis jiroveci pneumonia prophylaxis in AIDS patients – Sulfadoxine & pyrimethamine.

Adverse effects:

  • Skin rash (most common) – Due to hypersensitivity.
  • Cause granulocytopenia, thrombocytopenia & aplastic anemia (more common in HIV infected patients).
  • Cause acute hemolysis in patients with G-6 PD deficiency.
  • Crystalluria & Hematuria:
    • Solubility of sulfonamides decreases in acidic urine resulting in drug precipitation.
    • Minimum risk with soluble drugs like sulfisoxazole.
  • Selective bacterial toxicity:
    • Due to lack of ability of mammalian cells to synthesize folic acid & utilize preformed folic acid in diet.
  • Kernicterus in new born (if given in third trimester of pregnancy):
    • Due to bilirubin displacement from plasma protein binding sites.
  • SLE.

2. Trimethoprim:

  • Bacteriostatic antimetabolite inhibiting dihydrofolate reductase.
  • High concentrations in prostate & vaginal fluids.
  • Mostly combined with sulfonamides.
  • Given alone in prostatitis & UTI.
  • Cause megaloblastic anemia (can be ameliorated by folinic acid), leucopenia & pancytopenia.
  • Result in hyperkalemia  – Due to amiloride like action & inhibition of epithelial Na+ channels in collecting ducts.

3. Cotrimoxazole:

  • Fixed dose combination of sulfamethoxazole & trimethoprim in ratio of 5:1.
  • Bactericidal.
  • Plasma concentration of two drugs attained – 20:1.

MOA:

  • Due to sequential blockade at two steps in DNA synthesis
  • Sulfamethoxazole inhibits folate synthase; Trimethoprim inhibits DHFRase.

Uses:

  • DOC for pneumocystosis & nocardiosis.
  • Effective in UTI, respiratory tract infections, MRSA, middle ear & sinus infections.
    • Caused by Hemophilus & Moraxella.

Exam Important

  • Short-acting sulfonamides include Sulfisoxazole, sulfamethizole, sulfacytine.
  • Sulfadoxine is a long-acting sulfonamides.
  • Skin rash is the most common adverse effect of sulfonamide due to hypersensitivity.
  • Solubility of sulfonamides decreases in acidic urine resulting in drug precipitation causing Crystalluria & Hematuria.
  • Crystalluria risk is minimum with soluble drugs like sulfisoxazole.
  • Sulfonamides if given in third trimester of pregnancy result in kernicterus in new-born, due to bilirubin displacement from plasma protein binding sites.
  • Trimethoprim is a bacteriostatic antimetabolite inhibiting dihydrofolate reductase
  • Trimethoprim is highest concentration in prostate & vaginal fluids.
  • Trimethoprim due to amiloride like action results in megaloblastic anemia (ameliorated by folinic acid), hyperkalemia (inhibition of epithelial Na+ channels in collecting ducts).
  • Cotrimoxazole is bactericidal with fixed dose combination of sulfamethoxazole & trimethoprim in ratio of 5:1.
  • Sulfamethoxazole inhibits folate synthase.
  • Trimethoprim inhibits DHFRase.
  • Cotrimoxazole is DOC for pneumocystosis & nocardiosis.
Don’t Forget to Solve all the previous Year Question asked on ANTI-METABOLITES

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