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Macrolides

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Protein Synthesis Inhibitors

Macrolides Classification:

ErythromycinClarithromycinAzithromycinKetolides

Telithromycin (newer drugs)

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Antibacterial Activity (Erythromycin)These drugs are usually bacteriostatic but may be

bactericidal on high concentration against verysusceptible organisms.They are effective against aerobic gram positive bacilliand cocciS. pyogenesStreptococcus viridansClostridium perfringensCornybacterium diphtheriaListeria monocytogenesLess activity against gram negative including H.influenzae, N. meningitidis.

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Mechanism Of ActionIt is bacteriostatic sometimes bactericidalProtein synthesis is inhibited by binding

reversibly to 50S ribosomal sub-unitIt is believed that they do not inhibit peptide bondformation directly but rather inhibit thetranslocation step wherein a newly synthesized

peptidyl tRNA molecule moves from the acceptor site on the ribosome to the peptidyl (donor site).They can inhibit elongation of the protein by

blocking the translocation of the ribosome to the

next codon on the mRNA.

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Mechanism Of Action.

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Mechanism of development of resistanceThere are four mechanisms through whichdifferent bacteria develop resistance against

macrolidesEfflux of the drug by an active pump mechanismMethylase enzyme leads to ribosomal modificationand inability to bind the drugs to the site

Hydrolysis of macrolides by estrase produced byEnterobacteriaceaeAlteration of 50S ribosomal proteins bychromosomal mutation Bacillus sutilis,Compylobacter and gram positive cocci

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Pharmacokinetics:Ery thromycin:

Absorption:

Incompletely but adequately absorbed from upper part of small intestine, inactivated by gastric acidstherefore prepared as enteric coated tabs.Food increases GI acidity -- slows absorption.

High plasma concentrations can be obtained if given in injectable form.

Distribution:Diffuses readily into intracellular fluids, activitycan be achieved at essentially all sites EXCEPT

brain and CSF

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Elimination:The drug is excreted in active from only2%-5% in urineIt is mainly accumulated in Liver andexcreted in active form in bile.

Dose needs not be adjusted in renal patients.

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Therapeutic Uses of Erythromycin Dose ranges from 1 2g /d in divided doses every 6 hrs.may be increased to 8 g in case of severity of infection.Mycoplasma pneumoniae infectionsLigionnaires disease.

Drug of choice in pneumonia caused by ligionella sp.

Chlamydial infectionsDiphtheriaPertussis (drug of choice)Streptococcal infectionsStaphylococcal infectionsCompylobacter infectionsTetanus

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Prophylactic use:It may be used prophylactically in recurrenceof rheumatic fever in patients, or duringdental procedures, in patients with sensitivityto Benzyl Penicillin which is drug of choice

for that conditions.

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ClarithromycinIt is derived from erythromycin by addinga methyl group and has improved acidstability and oral absorption compared witherythromycin.

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Clarithromycin (continued)Spectrum: Similar to erythromycin EXCEPT it is more activeagainst mycobacterium avium. M. leprae Absorption:

It is absorbed rapidly from GITBioavailibility reduces to 50%-55% due to its rapid first-passmetabolism.The standard formulation may be given with or without food

Extended-release form of this drug which is given 1g once dailyshould be given with food which improves bioavailibility.

Distribution:After absorption it undergoes rapid first-pass metabolism to its activemetabolite 14-hydroxyclarithromycin. Both of these agents aredistributed widely throughout the body and achieve high intracellular

concentrations. Tissue concentrations usually exceed serum conc.

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Therapeutic uses of ClarithromycinThe advantages of clarithromycin compared with erythromycin are lower frequency of gastrointestinal intolerance and less frequent dosing. Except for the micro-organisms notified above the two drugs are therapeutically similar Helicobacter pylori infectionsMycobacterial infections ( first line therapy)TetanusSyphilisCompylobacter infectionsStreptococcal infections: Pharyngitis, scarlet fever etc

Staphylococcal infections, but can not be relied upon.Legionella infectionsMycoplasma infectionsProphylactic uses as described in erythromycinDOSE: 250 500mg twice daily depending upon age and severity of

infection.

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AzithromycinSPECTRUMSimilar to erythromycin with more activity against H.

influenzae and campylobacter, very active against M.catarrhalis, P. multocida, Chlamydia, M. Pneumoniae, L. pneumophila, B. burgdorferi, Fusobacterium and N.gonorrhoeae.

Enhanced activity against M. avium-intracellulare as wellas some protozoa e,g., Toxoplasma gondii,Cryptosporidium, and plasmodium.

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Pharmacokinetics (Azithromycin)Absorption:

Azithromycin administered orally is well absorbedfrom GIT and distributed widely throughout the bodyEXCEPT to cerebrospinal fluid.Administration with antacids esp. aluminum andmagnesium hydroxide will interfere with absorption (

not bioavailability)Dose : 250 500mg once daily

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Distribution:Its unique pharmacokinetic properties includeextensive tissue distribution and high drugconcentrations within cells (including phagocytes),resulting in much greater tissue or secretion drugconcentrations compared to simultaneous serum

concentrations.Tissue fibroblasts act as natural reservoirs of drug,and transfer of drug to phagocytes is easily achieved.Protein binding is low.

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Elimination:Still being elucidatedUndergoes some hepatic metabolism to inactivemetabolites, biliary excretion is the major route of elimination.Only 12% of the drug is excreted unchanged in urine.

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Therapeutic uses:Chlamydial infections:

Azithromycin is specifically recommended as an alternative todoxycycline in patients with uncomplicated urethral, endocervical,rectal, or epididymal infections.Pneumonia caused by Chlamydial pneumoniae

Diphtheria:Erythromycin is more effective

Mycobacterial Infections:Azithromycin or Clarithromycin are first line of therapy against

prophylaxis and treatment of disseminated infections caused by M.avium-intracellulare in AIDS pts. And treatment of pulmonarydisease in non-HIV-infected patients.

Other infections:Treatment and prophylaxis of toxoplasmosis encephalitis anddiarrhea due to Cryptosporidium.

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Adverse Effects Of Macrolides.GIT Effects:

Anorexia, nausea, vomiting and diarrhea oraladministration

Liver Toxicity:Erythromycin particularly can produce acutecholestatic hepatitis (fever, jaundice, impaired liver functions) probably as a hypersensitivity reaction.

Other Hypersensitivity reactions:Fever, eosinophilia and skin eruptions.

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Pharmacokinetics:Absorption:

Absorbed from GIT

Distribution:distributed in tissues and intracellular penetration

is good.Elimination:

Metabolized in the liver and eliminated bycombination of biliary and urinary routes.

Dose: 800mg single daily dose.

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Indications:Respiratory tract infections includingcommunity-acquired bacterial pneumonia,acute-on-chronic bronchitis, sinusitis,streptococcal pharyngitis.

Adverse effects:Cardiac effects more pronounced likeerythromycin

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