Macrolides

MACROLIDES


MACROLIDES

Structure:

  • Large cyclic lactone ring structure with attached sugars.

Drugs included:

  • Erythromycin, azithromycin, roxithromycin, fidaxomicin, tacrolimus & clarithromycin.
  • Tacrolimus – 
    • An immunosuppressant drug.
    • FK-506 commonly known as Tacrolimus.

MOA:

  • Drugs bind to 50S ribosome & block peptide chain translocation from A to P site.
  • Ketolides & lincosamides have similar mechanism of action.

Pharmacokinetics:

  • Well absorbed orally.
  • Drug excretion:
    • Excreted by biliary route – Erythromycin.
    • Excretion of urinary excretion – Azithromycin.
    • Excreted by both renal & biliary routes – Clarithromycin.
  • Half-life:
    • Azithromycin – Longest half-life; hence, administered as single daily dose.
    • Note: Erythromycin requires administered four times a day.

General drug effects:

  • An anti-inflammatory action:
    • Due to effect on neutrophils & inflammatory cytokines.
    • Hence, used in prevention of cystic fibrosis exacerbation.

Clinical Uses:

  • DOC for Chancroid by Haemophilus ducreyi – Azithromycin (single dose).
  • DOC for treatment of toxoplasmosis in pregnancy – Spiramycin.
  • Against Corynebacterium (diphtheria), Campylobacter, Legionella infections, Atypical pneumonia, Whooping cough by Bordetella pertussis – As second choice drugs to penicillins.
  • For treatment of C. difficile infection – Fidaxomicin.
  • Used in prevention of cystic fibrosis exacerbation.

Individual drugs:

1. Azithromycin:

  • More active against H. influenza & Neisseria.
  • Long half-life – hence, single dose is effective.
  • Not an enzyme inhibitor & free from drugs interactions.
  • Uses:
    • For treatment of urogenital infections, caused by chlamydia.
    • For prophylaxis of MAC infections – once weekly.

2. Roxithromycin:

  • Similar spectrum as of azithromycin.

3. Clarithromycin:

  • Useful for prophylaxis & treatment of Mycobacterium avium complex.
  • Treatment of peptic ulcer by H. pylori.

4. Fidaxomicin:

  • Non-absorbed macrolide.
5. Tacrolimus:
  • Indicated for prophylaxis of organ transplant rejection.
  • Glucose intolerance – Well-recognized side effect.

General adverse effects:

  • Gastro-intestinal effects – Most common for all macrolides.

Macrolide Toxicity:

  • Mainly by Erythromycin.
  • Erythromycin estolate implicated to cause acute cholestatic hepatitis, especially in pregnant females.  Other salts of erythromycin are safe.

MOA: Erythromycin, roxithromycin & clarithromycin inhibit CYP3A4.

Toxicity effects:

  • On administered to patients receiving terfenadine, astemizole or cisapride (substrates of CYP3A4):
    • Lead to QT interval prolongation & serious polymorphic ventricular tachycardia (torsades de pointes).
  • Intravenous erythromycin (not oral) – Cause dose-dependent reversible ototoxicity.

Other effects: 

  • Diarrhea – Due to motilin receptors stimulation.

Drug interactions:

  • Erythromycin increases plasma theophylline concentration, by inhibiting CYP1A2.

Exam Important

  • Erythromycin, azithromycin, roxithromycin, fidaxomicin, tacrolimus & clarithromycin are all macrolides.
  • Erythromycin is given in decreased bowel motility (diarrhea) because it binds to motilin receptors stimulation.
  • Tacrolimus is an immunosuppressant drug.
  • Macrolides bind to 50S ribosome & block peptide chain translocation from A to P site.
  • Azithromycin has longest half-life; hence, administered as single daily dose.
  • Due to their anti-inflammatory action, macrolides are used in prevention of cystic fibrosis exacerbation.
  • DOC for Chancroid by Haemophilus ducreyi is azithromycin (single dose).
  • DOC for treatment of toxoplasmosis in pregnancy is Spiramycin.
  • Macrolides are also effective against Corynebacterium (diphtheria), Campylobacter, Legionella infections, Atypical pneumonia, Whooping cough by Bordetella pertussis & are preferred as second choice drugs to penicillins.
  • Macrolide antibiotic that is used for treatment of C. difficile infection is Fidaxomicin.
  • Azithromycin is macrolide antibiotic more active against H. influenza & Neisseria.
  • Azithromycin has a longer half-life & its single dose is effective.
  • Azithromycin is not an enzyme inhibitor & free from drugs interactions.
  • Erythromycin estolate implicated to cause acute cholestatic hepatitis, especially in pregnant females.
  • Erythromycin, roxithromycin & clarithromycin inhibit CYP3A4.
  • Erythromycin on administering to patients receiving terfenadine, astemizole or cisapride (substrates of CYP3A4), can lead to QT interval prolongation & serious polymorphic ventricular tachycardia (torsades de pointes).
  • Intravenous erythromycin can cause dose-dependent reversible ototoxicity.
  • Erythromycin increases plasma theophylline concentration, by inhibiting CYP1A2.
  • Fk-506 is a macrolide antibiotic.
  • FK-506 commonly known as Tacrolimus.
  • Tacrolimus is indicated for prophylaxis of organ transplant rejection & its well-recognized side effect is glucose intolerance.
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