MACROLIDES Osource: Streptomyces erythreus OMechanism of action: * Macrolides bind with 50s subunit of bacterial ribosomal RNA. * Block the aminoacyl translocation reaction and formation of initiation complex. * Thus inhibit protein synthesis + May be bacteriostatic or bactericidal (high doses). Ol Pharmacokinetics: * Absorption — > Can be given orally > Erythromycin base is destroyed by stomach acid and so given as enteric coated form > Clarithromycin —Less incidence of gastrointestinal intolerance > azithromycin - Rapidly absorbeo and wel toleratec orally Should be given 1 hour before or 2 hour after meal > Serum half ife— a. Erythromycin-1.5 hours b. Clarithromycin — 6 hours . Atithromycin ~ 68 hours (app 3 days) Group of closely related compounds consist of macrocyclic lactone ring (14 Or 16 atoms) and deoxysugars. Drugs: 1. Erythromycin ~ Prototype 2. Clarithromycin ~ Semi-synthetic derivative of erythromycin 3. Azithromycin — Semi-synthetic derivative of erythromycin 4, Ketolides - Telithromycin @— amino > charged 1ANA > Erythromycin - + Widely distributed to tissues except CNS + itis taken up by neutrophil and macrophages ‘ang reaches the fetus but no teratogenic effect. + Traversesplacen > Clarithromycin ~Also distributed very well > Aaithromycin ~ + Penetrates into most tissues except CNS + Extremely wel penetration ito phagocytic cells + Tissue concentration: serum concentration = 10:1 + Slouly released from the tissue (tissue halflife 2-4 days) to produce an elimination half fe approximately 3 days + So this unique property permit ance daly dosing and shortening of duration of treatment (3 days)‘= Metabolism — > Metabolized inthe liver > Inhibits €P450 enzymes — + Erythromycin * Clarithromycin > Does not inhibit CP450 enaymes and no drug interact * Aaitheomyein Excretion — > Erythromycin ané Azithromycin * Large amounts excrete by bile, 5% excreted by urine + Adjustment for renal failure Isnt necessary > Clarithromycin ~ Excreted by kidney 5. Infections caused by Staphylococci in penicillin allergic patient - Erythromycin 6. As prophylaxis against endocarditis with valvular heart disease during dental procedure — Erythomycin, Clindamycin 7. Infections caused by M. aviurn complex — Clarithromycin > Erythromycin 8. Infections caused by M. leprae, T. gondii ~ Clarithromycin, Azithromycin 9. Peptic ulcer (triple therapy against H. pylori) 10. Infection caused by H. influenzae — Azithromycin is highly active 4. Drug interactions - + Erythromycin and Clarithromycin + Inhibit cP4so. * Increase serum concentration of Theophylline, Oral anti-coagulants, Cyclosporine, Methylprednisolone ‘+ Increase serum concentration of oral digoxin by increasing its bioavailability Q Clinical uses: 1. Diphtheria, Corynebacterial sepsis, Erythrasma (caused by C. diphtheriae) — Drug of choice 2. Respiratory, ocular, neonatal, genital infections (caused by Chlamydia) - Drug of choice (Azithromycin — highly active) 3. Pelvic infections in pregnancy, Cervicitis, Urethritis (caused by Chlamydia) - Drug of choice 4, Community acquired pneumonia (caused by Pneumococcus, Mycoplasma, Legionella CO Adverse effects: 1. GIT- Anorexia, Nausea, Vomiting, Diarrhoea (Direct stimulation of the gut) 2. Liver toxicity — Acute cholestatic hepatitis (fever, jaundice, Impaired liver function) — Particularly estolate (probably hypersensitivity reaction) 3. Allergic reaction — Fever, Eosinophilia, Rashes Advantages of clarithromycin over erythromycin: (Therapeutically similar) More acid stability Better oral absorption Longer half life (6 hours) Twice daily dosing Less incidence of Gl intolerance More active against M. avium complex More active against M. leprae, T. gondii Disadvantagi Cost - high roC1 Advantage of Azithromycin over other macrolides: Rapidly absorbed Well tolerated Long half life - 68 hours Long duration of action Once daily dose Short duration of therapy Does not activate CP450 enzymes No drug interaction Excreted by bile 10. Can be given in patient with renal insufficiency 2 MLS drugs: 1. Macrolide 2. Lincosemide - Clindamycin 3. Streptogrmine ~ + Quinupristin(streptogramine B) + Dalfopristin(streptogramine A) + Ratio = 30:70 = Structurally unrelated but mechanically similar compound = Share same ribosomal binding site Why short course of therapy? * Penetrates most tissues (except CSF) very well * Tissue concentration is 10 ~ 100 folds greater than serum concentration * Drugs slowly released from tissues (tissue half life is 2-4 days) * Elimination half life Approximately 3 days * This unique property permits once daily dosing and short course of therapy