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.

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.

Don’t Forget to Solve all the previous Year Question asked on MACROLIDES