Macrolide antibiotics

Pharmacology of Macrolide antibiotics

1. macrolides G Vijay Narasimha Kumar Asst. Professor, Dept . of . Pharmacology Sri Padmavathi School of Pharmacy

2. INTRODUCTION The Macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxysugars are attached. The prototype drug Erythromycin, which consists of two sugar moieties attached to a 14-atom lactone ring.

3. It was obtained in 1952 from Streptomyces erythreus . Clarithromycin and Azithromycin are semisynthetic derivatives of Erythromycin.

4. CLASSIFICATION MACROLIDES ERYTHROMYCIN CLARITHROMYCIN AZITHROMYCIN ROXITHROMYCIN SPIRAMYCIN KETOLIDES TELITHROMYCIN

5. MECHANISM OF ACTION Inhibits protein synthesis by reversibly binding to the 50S ribosomal subunit Suppression of RNA-dependent protein synthesis by inhibition of translocation of mRNA. Typically bacteriostatic activity Bactericidal at high concentrations against very susceptible organisms

6. SPECTRUM OF ANTIBACTERIAL ACTIVITY Macrolides are similar to Penicillins regarding their spectrum of activity. They are effective against Penicillin-resistant strains. GRAM +VE COCCI GRAM +VE BACILLI Streptococcus pneumoniae , Bacilus anthracis , Strepto . pyogens Listeria monocytogenes Staphylococci ( most or penicillin resistant species and these are now macrolide resistant also) Clostridium tetani GRAM –VE COCCI GRAM -VE BACILLI Nesseria gonorrhoeae Legionella pneumophila Moraxella catarrhalis Bordetella pertussis Bartonella henselae Haemophilus influenzae , h. ducreyi . Campylobacter jejuni Helicobacter pylori

7. ACID FAST BACILLI SPIROCHETES MISCELLANEOUS Mycobacterium kanasii Treponema pallidum Mycoplasma pneumoniae Mycobacterium avium intracellulare Ureaplasma urealyticum Mycobacterium avium complex Chlamydia trachomatis Mycobacterium leprae Chlamydia pneumoniae Chlamydia psittaci

8. BACTERIAL RESISTANCE Methylation of a guanine residue on ribosomal RNA leads to lower affinity toward Macrolides A n active efflux system Presence of a plasmid-associated Erythromycin esterase.

9. Clarithromycin and Azithromycin show cross-resistance with Erythromycin, but Telithromycin can be effective. Against Macrolide -resistant organisms. Lack of cell wall permeability to Macrolides is the reason why G(-) bacteria are resistant to antibacterial effects of these agents.

10. PHARMACOKINETICS ABSORPTION ERYTHROMYCIN – variable absorption, food may decrease the absorption. Base: destroyed by gastric acid; Enteric coated Esters and ester salts: more acid stable CLARITHROMYCIN – acid stable and well-absorbed regardless of presence of food. AZITHROMYCIN –acid stable, food decreases absorption of capsules.

11. DISTRIBUTION: Extensive tissue and cellular distribution Clarithromycin and Azithromycin with extensive penetration . No BBB and CSF penetration Erythromycin accumulates in the prostatic fluid and also in macrophages. Azithromycin accumulates in Neutrophils, Macrophages, Fibroblasts. Has Large volume of distribution and longest half life (greater than 40 hrs )

12. ELIMINATION: Clarithromycin is the only Macrolide partially eliminated by the Kidney(18% of parent and all metabolites). Hepatically eliminated: ALL. NONE of the macrolides are removed during hemodialysis Erythromycin and Azithromycin are primarily concentrated and excreted through bile as active drugs .

13. Administration and fate of the Macrolide antibiotics.

14. ADVERSE EFFECTS GASTROINTESTINAL EFFECTS: Anorexia, nausea, vomiting, and diarrhoea occasionally accompany oral administration. Gastrointestinal intolerance, which is due to a direct stimulation of gut motility, is the most common reason for discontinuing Erythromycin and substituting another antibiotic.

15. LIVER TOXICITY: Erythromycins, particularly the estolate , can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Most patients recover from this, but hepatitis reoccurs if the drug is Re administered. Macrolides get deposited in perilymph and causes ototoxicity . Other allergic reactions include fever, eosinophilia , and rashes. Prolong QT WAVE

16. DRUG INTERACTIONS Erythromycin metabolites can inhibit cytochrome P450 enzymes and thus increase the serum concentrations of numerous drugs including, Theophylline , Oral anticoagulants, Cyclosporine, and Methylprednisolone , Erythromycin increases serum concentrations of oral Digoxin by increasing its bioavailability.

17. THERAPEUTIC USES OF ERYTHROMYCIN It is used to treat The upper part of the respiratory tract infections, Soft tissue G(+) infections, Urethritis caused by ( MRSA , Ureaplasma Urealyticum ) Mycoplasma pneumonia caused pneumonia, Campylobacter jejuni -- Enteritis,

18. e. Chlamydia infections Majorly C. Trachomatis - ( may result in Urethritis , epididymitis, cervicitis, pelvic inflammatory disease (PID) and other conditions. ) C. Pneumonia – causes respiratory illness ( prolonged cough, bronchitis, and pneumonia as well as a sore throat, laryngitis, ear infections, and sinusitis ) f. Gonorrhoea caused by Nesseria gonorrhoea g. Treatment and prophylaxis of ophthalmic infections and also neonatal conjuctivitis

19. h. To treat acne i . Pelvic inflammatory disease due to susceptible organisms (e.g., Streptococcus Pneumoniae , Streptococcus pyogenes , Haemophilus influenzae , Chlamydia, Legionella, Mycoplasma, Nesseria gonorrhoeae , Treponema )

20. ADVERSE DRUG REACTIONS: Ventricular arrhythmias, QT interval prolongation, Pseudomembranous colitis, Nausea/Vomiting, abdominal pain, cramping, diarrhea , hepatitis, rash, pruritis , phlebitis at IV site, allergic reactions.

21. THERAPEUTIC USES OF ROXITHROMYCIN Roxithromycin has same spectrum as of Erythromycin but it is more potent against moraxella catarrhalis and legionella and less potent against bordetella pertusis THERAPEUTIC USES OF SPIRAMYCIN It also resembles Erythromycin in its spectrum, though it has weaker activity. However, it is highly efficacious against toxaplasma gondii and c ryptosporidium causes Waterydiarrhoea with abdominalcramps .

22. CLINICAL APPLICATIONS OF CLARITHROMYCIN It is used to treat Respiratory tract infections ( pharyngitis /tonsillitis ). skin/skin structure infections due to susceptible organisms (e.g., S. pneumo , S. pyogenes , S. aureus , M. catarrhalis , Hemophilus influenza, Chlamydia pneumoniae , Mycoplasma ). To prevent or treatment of disseminated MAC infection.( Anemia is common in patients with disseminated MAC disease)

23. d. To Eradicate of H. pylori associated with peptic ulcer disease. ADVERSE DRUG REACTIONS : Hepatic failure, Pseudomembranous colitis, Stevens-Johnson syndrome, Toxic epidermal necrolysis , Drug rash (with eosinophilia )

24. THERAPEUTIC USES OF AZITHROMYCIN It has an extended spectrum compared to Erythromycin. It has a higher activity against C hlamydia trachomatis, Mycoplasma pneumoniae , Nesseria gonorrhoeae , toxoplasma gondii . Campylobacter jejuni ( It is among the most common bacterial infections of humans, often a  foodborne illness.) H. Influenza ( Bacteremia , Meningitis,Epiglotittis , Cellulitis , Infectious arthritis). Moraxella catarrhalis ( can cause infection  of the respiratory system, middle ear, eye, central nervous system).

25. It is used to acute bacterial infection Single dose treatment mild to moderate sinusitis Chancroid ( STD; Caused by haemophilus ducreyi ) To treat non gonococcal infections ( urethritis , cervicitis ) Prevention or treatment of MAC infection in patients with advanced HIV. ADVERSE REACTIONS: Pseudomembranous colitis, Abdominal pain, Nausea /Vomiting, Rash

26. Thank you