Macrolides

bacterial cell wall inhibitors, azithromycin, clarithromycin, roxithromycin

1. Jagir R. Patel Asst Professor Dept of Pharmacology M acrolides

2. Classification The  macrolides  are a class of natural products that consist of a large  macrocyclic  lactone ring to which one or more deoxy sugars, usually  cladinose and  desosamine, may be attached.  They are class of Protein synthesis inhibitors

3. Mechanism of Action Preventing the Transfer of the Peptidyl tRNA from the A-site to the P-site. Promotion of Peptidyl tRNA Dissociation Blocking Peptidyl Transferase. Preventing Ribosomal Assembly

4. Mechanism of Resistance

5. E rythromycin Erythromycin – Mainly effective on G+ bacteria A. Gram- positive bacteria Staph. Aureus S. pneumoniae URTIs ( eg . Otitis media, pharyngitis ) LRTIs (eg.Pneumoniae ) S. Pyrogens C. diphtheria B. Gram- negative bacteria T. pallidum C. Intracellular organisms L. pneumophila M. pneumoniae C. trachomatis Absorption:   Variable and unreliable due to instability in gastric acid. Food may reduce absorption of the base or the stearate. Time to peak plasma concentration: 1-4 hr. Distribution:   Widely distributed into body tissues and fluids. Crosses the placenta and enters breast milk. Metabolism:   Partly metabolised in the liver via  N -demethylation to inactive, unidentified metabolites. Excretion:   Via faeces and urine (as unchanged drug). Plasma half-life: 1.5-2.5 hr.

6. Interactions: erythromycin+ benzodiazepines= increase sedation erythromycin+ calcium channel blockers = Hypotension , Brady arrhythmia Indications: Respiratory tract infections Skin and soft tissue infections Susceptible infections Acne Prophylaxis of streptococcal infections in patients with evidence of rheumatic fever or heart disease Treatment and prophylaxis of ophthalmic infections and neonatal conjunctivitis

7. C larithromycin Antibacterial spectrum A. Gram- positive bacteria Staph. Aureus S. Pneumoniae S. Pyrogens B. Gram- negative bacteria H. influenzae H. Pylori M. catarrhalis C. Intracellular organisms M. pneumoniae L. Pneumophila Absorption:   Rapidly absorbed from the GI tract. Food delays rate of absorption. Bioavailability: Approx 50%. Distribution:   Widely distributed into most body tissues. Enters breast milk and distributed into CSF. Plasma protein binding: Approx 42-70%. Metabolism:   Partially hepatic converted to 14-hydroxyclarithromycin (active metabolite). Excretion:   Via urine and faeces Plasma half-life: 3-7 hr (clarithromycin), 5-9 hr (14-hydroxyclarithromycin). Interaction : Clarithromycin + zidovudine = Decreased concentration of zidovudine Indications : Respiratory tract infections; Skin and soft tissue infections ; Susceptible infections, Eradication of H. pylori associated with peptic ulcer disease, Respiratory tract infections; Skin and soft tissue infections 

8. Azithromycin Azithromycin is a semisynthetic azalide antibiotic . Antibacterial spectrum A. Gram- positive bacteria Staph. Aureus S. Pneumoniae S. Pyrogens B. Gram- negative bacteria (> erythromycin) M. catarrhalis H. influenzae C. Intracellular organisms (> erythromycin) L. Pneumophila M. pneumoniae Chlamydia speci es Absorption :  Rapidly absorbed from the GI tract. Reduced by food . bioavailability: Approx 34-52%. Time to peak plasma concentration: Oral tab: 2-3 hr; IV: 1-2 hr. Distribution :  Extensive into the tissues (higher than those in blood), CSF (small amounts).Plasma protein binding: 7-51% (oral and IV). Metabolism:   Hepatic metabolism via demethylation. Excretion:   Via bile urine. Terminal elimination half-life: About 68 hr. Interaction : Increases serum concentrations of digoxin, ciclosporin, hexobarbital and phenytoin. 

9. Indications: Skin and soft tissue infections Respiratory tract infections Uncomplicated genital infections due to Chlamydia trachomatis Non- gonococcal cervicitis/urethritis due to Chlamydia trachomatis Chancroid , Uncomplicated Gonorrhoea, Active immunization against typhoid fever caused by Salmonella typhi, Community-acquired pneumonia Bacterial conjunctivitis

10. Telithromycin Telithromycin is a semisynthetic ketolide antibiotic that blocks protein synthesis by binding to domains II and V of 23S ribosomal RNA of the 50S ribosome subunit. It may also inhibit the assembly of nascent ribosomal units . Absorption:  Rapidly absorbed from the GI tract. Bioavailability: 57%. Time to peak plasma concentration: Approx 1-3 hr. Distribution :  Widely distributed in body fluids and tissues, including the resp tract .. Plasma protein binding: 60-70 %. Metabolism :  Undergoes hepatic metabolism to 4 major metabolites Excretion :  Via urine (13% as unchanged drug; remainder as metabolites) and faeces (7%). Elimination half-life: 2-3 hr. Terminal half-life: Approx 10 hr . Interactions: Additive effect on QT interval prolongation w/ class 1A (e.g. quinidine, procainamide) or class III (e.g. dofetilide) antiarrhythmic agents Indications: Community-acquired pneumonia

11. Roxithromycin Absorption :  oral reduced if taken after food. Bioavailability: about 50 %. Distribution:  Widely distributed into body tissues and fluids . Metabolism:  Small amounts are metabolised in the liver . Excretion:  Mainly via the faeces as unchanged drug and metabolites, via the urine & the lungs Elimination half-life: 8-13 hr. Interactions : May raise serum levels of ciclosporin and digoxin Susceptible infections

12. Common Adverse E ffects