1. MACROLIDES

2. INTRODUCTION
Belong to the Polyketide (produced by fungi) class of natural products.
A group of antibiotics consisting of a macrolide ring
A large lactone ring to which one or more deoxy sugars, are attached.
The lactone ring can be either 14, 15 or 16 membered.
MACROLIDES:-
ERYTHROMYCIN
CLARITHROMYCIN
AZITHROMYCIN
ROXITHROMYCIN

3. ERYTHROMYCIN

4. ERYTHROMYCIN Isolated from Streptomyces erythreus in 1952
A drug of choice and an alternative to penicillin in individuals who are allergic to β-lactam antibiotics
Slightly water soluble
Stable in aqueous solutions at or below room temperature
Unstable in acidic or basic conditions or at high temperatures.

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
More active in alkaline medium
After peptide bond formation between the newly attached amino acid and the nacent peptide chain at the acceptor (A) site the elongated peptide is translocated back to the peptidyl (P) site, making the A site available for next aminoacyl tRNA attachment.
This is prevented by erythromycin and the ribosome fails to move along the mRNA to expose the next codon.
As an indirect consequence, peptide chain may be prematurely terminated: synthesis of larger proteins is specifically suppressed.

6. Mechanism of action

7. RESISTANCE Becoming a serious problem Several mechanisms are:
ANTIMICROBIAL SPECTRUM :-
Narrow spectrum
Mostly gram-positive
Few gram-negative bacteria
Highly active against:- Str. pyogenes and Str. pneumoniae, N. gonorrhoeae, Clostridia, C. diphtheriae, Listeria.
Sensitive :- penicillin-resistant Staphylococci and Streptococci were
Highly sensitive that are not affected by penicillin:- Campylobacter, Legionella, Branhamella catarrhalis, Gardnerella vaginalis and Mycoplasma.
Moderately sensitive :- H. influenzae, H. ducreyi, B. Pertussis,Chlamydia trachomatis, Str. viridans, N. Meningitidis and Rickettsiae
RESISTANCE
Becoming a serious problem
Several mechanisms are:
Less permeable
Presence of efflux pump
Decreased affinity by plasmid encoded methylase enzyme
Presence of plasmid associated erythromycin esterase
Change in the 50S ribosome by chromosomal mutation
Cross-resistance occurs between all macrolides

8. PHARMACOKINETICS Concentrates in liver
Erythromycin is acid labile but all others (newer) are stable
Given as enteric coated tablets
Food delays absorption
Its acid esters are better absorbed
Widely distributed in the body except CSF
Diffuses into prostatic fluid, accumulates in macrophages
Concentrates in liver
Inflammation allows greater tissue penetration
70-80% plasma protein bound
Renal excretion is minor (5%)
Its plasma t1/2 is 1.5hr, but it persists longer in tissues

9. ADVERSE EFFECTS 1 . Gastrointestinal Mild-to-severe epigastric pain
Diarrhoea
2. Reversible hearing impairment-Very high doses
3. Hypersensitivity
Rashes and fever are infrequent.
4. cholestatic jaundice (caused by thickened bile or bile plugs in the small biliary passages of the liver)

10. INTERACTION Erythromycin inhibits hepatic oxidation of many drugs
rise in plasma levels of theophylline, carbamazepine, valproate, ergotamine and warfarin.
To inhibition of CYP3A4 by erythromycin/ clarithromycin
Q-T prolongation, serious ventricular arrhythmias and death
due resulting in high blood levels of concurrently administered terfenadine (allergic inflammation of the nasal airways) / astemizole ( antihistamine drug)/ cisapride (treatment of gastroesophageal reflux disease).

11. INTERACTIONS

12. USES A . As an alternative to penicillin
1. Streptococcal pharyngitis, tonsillitis, mastoiditis and community acquired respiratory infections caused by pneumococci and H. influenzae respond equally well to erythromycin.
It is an alternative drug for prophylaxis of rheumatic fever and SABE.
2. Diphtheria (causing inflammation of the mucous membranes, )
3. Tetanus (marked by rigidity and spasms of the voluntary muscles)
4. Syphilis and gonorrhoea
5. Leptospirosis

13. C. As a second drug choice:
B. As a first choice drug for
1 . Atypical pneumonia caused by Mycoplasma pneumoniae
2. Whooping cough:- treatment for eradicating B. pertussis from upper respiratory tract.
3. Chancroid
C. As a second drug choice:
Campylobactor enteritis
Legionnaire’s pneumonia
Chlamydia trachomitis
Pencillin resistant Staphylococcal infections

14. Short elimination half-life Gastric acid liability
PROBLEMS WITH ERYTHROMYCIN
Acid labile
Narrow spectrum
Poor GI tolerance
Short elimination half-life
Gastric acid liability
Low oral bioavailability
Poor tissue penetration
Advantages of New macrolides
Broader spectrum
Orally effective
High blood concentration
Longer t 1/2
Less toxicity

15. ROXITHROMYCIN Semisynthetic long-acting Acid-stable
Antimicrobial spectrum resembles with erythromycin.
More potent against
Branh. catarrhalis, gard. vaginalis and Legionella
less potent against
B. pertussis.
Good eternal absorption
Good tissue penetration
Plasma t1/ hr
Better gastric tolerability
Affinity for cytochrome P450 is lower,
Drug interactions are not ruled out.
An alternative to erythromycin
For respiratory, ENT, skin and soft tissue and genital tract infections with similar efficacy.

16. ROXITHROMYCIN

17. CLARITHROMYCIN

18. CLARITHROMYCIN Antimicrobial spectrum similar to erythromycin
In addition includes
Mycobact. avium complex (MAC),
other atypical mycobacteria,
Mycobact. leprae and
some anaerobes
but not Bact. Jragilis.
More active against
sensitive strains of gram-positive cocci,
Moraxella,
Legionella,
Mycoplasma pneumoniae
Helicobacter pylori.
Bacteria resistance to erythromycin are resistant to clarithromycin also.
More acid-stable
Rapidly absorbed
Oral bioavailability is -50% due to first pass metabolism
Food delays but does not decrease absorption.
Greater tissue distribution than erythromycin
Plasma t1/2 of 6-9 hours
An active metabolite is produced
Excreted unchanged in urine

19. INDICATIONS SIDE EFFECTS Upper and lower RTI Sinusitis Otitis media
Whooping cough
Pneumonia
Skin and skin structure infections due to Strep. pyogenes and some Staph. aureus.
First line drug in combination regimens for MAC infection in AIDS patients
Second line drug for other mycobacterial diseases as well as leprosy
SIDE EFFECTS
Similar to erythromycin,
But gastric tolerance is better.
High doses can cause reversible hearing loss.
Pseudomembranous enterocolitis (inflammation of the large intestine)
Hepatic dysfunction or rhabdomyolysis (the destruction of striated muscle cells).
Drug interaction is similar to erythromycin.

20. AZITHROMYCIN

21. AZITHROMYCIN Not active against erythromycin resistant bacteria
Expanded spectrum
Improved pharmacokinetics
Better tolerability
Improved drug interaction profiles
SPECTRUM:-
More active than other macrolides against H. influenzae,
But less active against gram-positive cocci
High activity on respiratory pathogens-
Mycoplama,
Chlamydia pneumoniae,
Legionella,
Moraxella
others like Campylobacter, Ch. Trachomatis, H. ducreyi, Calymm, granulomatis, N. gonorrhoea
Not active against erythromycin resistant bacteria
Penicillinase producing St. aureus are inhibited.
Good activity is against MAC
PHARMACOKINETICS:-
Acid-stability,
Rapid oral absorption
Marked tissue distribution
Intracellular penetration
T1/2 of >50 hr.
Largely excreted in bile
Renal excretion is - 10%

22. Abdominal pain (less than erythromycin), Headache Dizziness.
INDICATIONS
As first choice over erythromicin
(a) Legionnaires' pneumonia
(b) Chlamydia trachomatis
(c). Donovanosis (characterized by ulcerative genital lesions) caused by Calymmatobacterium granulomatis
The other indications :-
Pharyngitis,
Tonsillitis,
Sinusitis,
Otitis media,
Pneumonias,
Chronic bronchitis,
Streptococcal and some staphylococcal skin and soft tissue infections.
Effective in the prophylaxis and treatment of MAC in AIDS patients.
Other potential uses are in
Typhoid,
Oxoplasmosis
Malaria.
SIDE EFFECTS
Mild gastric upset,
Abdominal pain (less than erythromycin),
Headache
Dizziness.
Not affecting hepatic CYP3A4 enzyme.

23. THANK YOU - PHARMA STREET