Macrolide antibiotics

Macrolides are a class of antibiotics derived from Saccharopolyspora erythraea (originally called Streptomyces erythreus), a type of soil-borne bacteria.

1. Macrolide Antibiotics Presented By: Gandham Malasree M Pharmacy Regd no: 620209502002 Dept of Pharmaceutical Chemistry Under the guidance of: Dr. M. Murali Krishna Professor Dept of Pharmaceutical Chemistry AU COLLEGE OF PHARMACEUTICAL SCIENCES, VISAKHAPATNAM

2. MACROLIDES Macrolides are a class of antibiotics derived from Saccharopolyspora erythraea (originally called Streptomyces erythreus ), a type of soil-borne bacteria. Macrolides are macrocyclic lactone ring molecules. They belong to the class of polyketide of natural products. The first identified macrolide is PICROMYCIN in year 1950. The second identified macrolides are ERYTHROMYCIN & CARBOMYCIN in the year 1952 . Some macrolides are identified from soil samples. Eg ; 1) Spiramycin 2) Josamycin 3) Rosamycin These macrolides are clinically inferior than erythromycin and its derivatives.

3. Chemistry Of Macrolides Macrocyclic lactone is a cyclic ester i.e cyclic carboxylic ester Formed from intramolecular esterification of hydroxy carboxylic acid C OH OH C O O O - H20

4. Macrolide Is having 3 parts Lactone ring Ketone group Glycosidically linked amino sugars It is a large non-planar strainless ring with 12-16 atoms It is having 2 deoxy sugars 1) L- Cladinose (neutral sugar) 2) d- Desosamine (amino sugar) The amino group present is dimethyl amino group . It forms salts with acids. Eg : 1) Glucoheptanoic acid 2) Lactobionic acid Aglycone part Glycone part

5. General structure of macrolide d- Desosamine L- Cladinose Macrocyclic lactone ring

6. Classification Of Macrolides 12 membered ring 14 membered ring 15 membered ring 16 membered ring 17 membered ring Methymycin Neomethymycin Natural compounds Erythromycin Oleandomycin Sporeamicin Semi synthetic compounds Roxithromycin Dirithromycin Flurithromycin Clarithromycin Azithromycin Natural compounds Spiramycin Josamycin Midecamycin Kitsamycin Semi synthetic compounds Rokitamycin Miokamycin Azithromycin Lankacidin complex

7. Special group of macrolides Azilides Triamilides Ketolides Azithromycin 15 membered ring Lactone ring + methylated nitrogen Tulathromycin 13-15 membered ring Telithromycin Cethromycin Solithromycin These are derivatives of erythromycin Cladinose + ketone group Lactone + cyclic carbamate group

8. Mechanism of action Macrolides binds with 50s ribosomal subunit (i.e., bind with 23s rRNA in the polypeptide exit tunnel i.e., adjacent to peptidyl transferase center in the 50s ribosomal subunit ) Inhibits peptidy transferase activity Interferes with translocation of aminoacids during translocation & assembly of protiens Inhibits protein synthesis

9. Erythromycin was isolated in the year 1952 from Streptomyces erythreus . Erythromycin is widely used as a substitute to penicillin in cases where patients were allergic to penicillin or had penicillin-resistant illnesses. Erythromycin is bacteriostatic. Erythromycin and its derivatives: Erythromycin Clarithromycin Azithromycin these are having superior pharmacokinetic properties because of their enhanced acid stability and improved distribution properties. ERYTHROMYCIN

10. Clinically used macrolides are Erythromycin Clarithromycin Azithromycin Dirithromycin Oleandomycin Limitation: Limitaion of erythromycin is acid instability forms internal cyclic ketal leads to formation of 6,9 ; 9,12 pyroketal derivative i.e., anhydro erythroycin

11. Structure of Erythromycin

12. Classification Of Erythromycin R1 R2 Type of erythromycin R1 R2 A -OH -OCH3 B -H -OCH3 C -OH -OH D -H -OH

13. Mechanism Of Action OF Erythromycin Macrolides binds with 50s ribosomal subunit (i.e., bind with 23s rRNA in the polypeptide exit tunnel i.e., adjacent to peptidyl transferase center in the 50s ribosomal subunit ) Inhibits peptidy transferase activity Interferes with translocation of aminoacids during translocation & assembly of protiens Inhibits protein synthesis

14. PHARMACOKINETICS: Erythromycin is destroyed by gastric acid. Food interferes with absorption. It is available in the form of stearates and esters and they are fairly acid satble . Half life – 1.5hrs Large amount of drug is secreted in bile excreted through feces only 5% of drug is excreted by the kidney through urine Dose adjustment is not required in renal insufficiency patients. It enters into neutrophils and macrophages. This drug crosses placenta.

15. RESISTANCE: Resistance is exhibited by 3 mechanisms Reduced permeability / increased efflux Production of esterases Ribosomal protection Cross resistance is between erythromycin and other macrolides Also between clindamycin and streptogramins Cross-resistance to macrolides, lincosamides , and streptogramins (an MLS resistant phenotype) it is due to acquired resistance can be either plasmid-mediated or chromosomal, i.e., through mutation.

16. SAR Of Erythromycin 1 2 3 4 5 14 13 12 11 10 9 8 7 6 1 2 3 4 4 5 5 2 3 1 6 6

17. Uses: Diptheria Chlamydia Pertusis Commonly acquired pneumonia Ear infections in children D ental abscesses S exually transmitted  infections. Adverse Drug Reactions: Nausea, vomiting, anoerexia , diarrhoea Increased GI disress Hypersensitivity reactions ( fever, rash) Torsade de pointes IHPS (Infantile hypertrophic pyloric stenosis) in infants.

18. Contraindications Macrolides are contraindicated in patients who have had an allergic reaction to them. Concomitant administration of macrolides with astemizole , cisapride , pimozide, or terfenadine is contraindicated because potentially fatal cardiac arrhythmias ( eg , QT prolongation, ventricular tachycardia, ventricular fibrillation, torsades de pointes) may occur when clarithromycin or erythromycin is given with these drugs. This effect is most likely due to inhibition of metabolism of these drugs by erythromycin and clarithromycin Interactions Macrolides should not be taken with colchicine as it may lead to colchicine toxicity. Symptoms of colchicine toxicity include gastrointestinal upset, fever, myalgia, pancytopenia, and organ failure.

19. It is a semi synthetic derivative of erythromycin. Azithromycin is a prototype of azalides. It is more active against chlamydial infections. Formation of Azithromycin: Erythromycin Erythromycin 9-oxime Beckmann rearrangement azithromycin Azithromycin Reduction of ring expanded lactum + N-methylation 15 membered ring intermediate is formed

20. Ring expanded analogue of erythromycin Tertiary amine nitrogen group Inserted between C-9 & C-10 & removal of carbonyl at C-9 Increases the stability of azithromycin to acid catalysed degradation Increases lipid solubility of molecules Does not form internal cyclic ketal

21. Structure of Azithromycin

22. Pharmacokinetics: Half life- 3-4 days Once daily dosing is sufficient and it is better when compared to clarithromycin. It is given 1hr before or 2hrs after food ( gastric acid inactivates macrolides). Uses: Treatment of urogenital and other sexually transmitted infections caused by Chlamydia trachomitis Neisseria gonorrhea Haemophilus ducreyi Urea plasma urealyticum Middle ear infections Streptococcal pharyngitis Commonly acquired pneumonia Travellers diarrhoea Prevention or treatment of MAC infection in patients with advanced HIV.

23. Side effects: Mild gastric upset Abdominal pain Headache Dizziness Interactions: Azithromycin with theophylline , carbamazepine, warfarin, ternifadine , and cisapride are not likely. Contraindications: Pharyngitis Tonsillitis Sinusitis CAP Chronic bronchitis

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