2. INTRODUCTION
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.
THE LACTONE RINGS ARE USUALLY 14-, 15-, OR 16-MEMBERED.
MACROLIDES BELONG TO THE POLYKETIDE CLASS OF NATURAL
PRODUCTS.
SOME MACROLIDES HAVE ANTIBIOTIC OR ANTIFUNGAL ACTIVITY AND
ARE USED AS PHARMACEUTICAL DRUGS. MACROLIDES ARE
BACTERIOSTATIC IN THAT THEY SUPPRESS OR INHIBIT BACTERIAL
GROWTH RATHER THAN KILLING BACTERIA COMPLETELY.
3. HISTORY
• THE FIRST MACROLIDE DISCOVERED WAS ERYTHROMYCIN, WHICH WAS
FIRST USED IN 1952 FROM STREPTOMYCES ERYTHREUS.
• ERYTHROMYCIN WAS WIDELY USED AS A SUBSTITUTE TO PENICILLIN IN
CASES WHERE PATIENTS WERE ALLERGIC TO PENICILLIN OR HAD
PENICILLIN-RESISTANT ILLNESSES.
• LATER MACROLIDES DEVELOPED, INCLUDING AZITHROMYCIN AND
CLARITHROMYCIN, STEMMED FROM CHEMICALLY MODIFYING
ERYTHROMYCIN; THESE COMPOUNDS WERE DESIGNED TO BE MORE
EASILY ABSORBED AND HAVE FEWER SIDE-EFFECTS (ERYTHROMYCIN
CAUSED GASTROINTESTINAL SIDE-EFFECTS IN A SIGNIFICANT
PROPORTION OF USERS).
4. CHEMISTRY AND CLASSIFICATION OF
MACROLIDES
• ACCORDING TO THE CARBON NUMBER OF LACTONE RING, MACROLIDES ARE
CLASSIFIED INTO 5 TYPES-
1) 12-MEMBERED RING MACROLIDES
2) 13-MEMBERED
3) 14-MEMBERED (MOST DRUGS)
4) 15-MEMBERED
5) 16-MEMBERED (MOST DRUGS)
BESIDES SOME SPECIAL GROUPS ARE AVAILABLE-
• AZALIDES: 15 MEMBERED, E.G- AZITHROMYCIN
• TRIAMILIDES: COMBINATION OF 13- AND 15-MEMBERED, E.G- TULATHROMYCIN.
• KETOLIDES: 14-MEMBERED WITH 3 KETONE GROUP, E.G- TELITHROMYCIN.
5. • MACROCYCLIC LACTONE RING
DEOXY
SUGARS
• DEOXY SUGARS ARE ATTACHED TO LACTONE RING BY GLYCOSIDIC BOND
8. • MACROLIDES ARE PROTEIN SYNTHESIS INHIBITORS.
• THE MECHANISM OF ACTION OF MACROLIDES IS INHIBITION OF BACTERIAL PROTEIN
BIOSYNTHESIS, AND THEY ARE THOUGHT TO DO THIS BY
• PREVENTING PEPTIDYL TRANSFERASE FROM ADDING THE GROWING PEPTIDE
ATTACHED TO T-RNA TO THE NEXT AMINO ACID(SIMILARLY TO CHLORAMPHENICOL
• AS WELLAS INHIBITING BACTERIAL RIBOSOMAL TRANSLATION.
• DUE TO PROTEIN INHIBITION MACROLIDES ARE CONSIDERED BACTERIOSTATIC
• HOWEVER AT A HIGHER CONCENTRATION OR LOW BACTERIAL DENSITY THEY CAN BE
BACTERICIDAL.
• MACROLIDES ARE IMMUNOMODULATORY
The peptidyl transferase is an aminoacyltransferase
as well as the primary enzymatic function of the
ribosome, which forms peptide bonds between
adjacent amino acids using tRNAs during the
translation process of protein biosynthesis.
9. ANTIBIOTIC
MACROLIDES
NON ANTIBIOTIC
MACROLIDES
ANTIFUNGAL DROPS TOXIC MACROLIDES
Azithromycin Tacrolimus Nystatin Mycolactones
Clarithromycin Sirolimus Amphotericin B Produced by
bacterias
Erythromycin Used as
immunosupessants
Or
immunomodulators
Are subgroup of
macrolides
10. PHARMACOKINETICS
Erythromycin
• Variable absorption
food may decrease
the absorption
• Base ; destroyed by
gastric acid
Clarithromycin
• Well absorbed
regardless of
presence of food
• Acid stable
Azithromycin
• Food decreases
absorption
• Acid stable
ABSORPTION
11. DISTRIBUTION
• EXTENSIVE TISSUE AND CELLULAR DISTRIBUTION
• NO BBB AND CSF PENETRATION
• CAN CROSS PLACENTA
• ERYTHROMYCIN ACCUMULATES IN PROSTATIC FLUID AND MACROPHAGES
• AZITHROMYCIN ACCUMULATES IN NEUTROPHILS, MACROPHAGES, FIBROBLASTS
12. METABOLISM
• VIA LIVER
• EXTENSIVELY METABOLIZED WITH EXCEPTION OF AZITHROMYCIN
• INHIBITS OXIDATION OF NUMBER OF DRUGS THROUGH ITS
INTERACTION WITH CYP-450 SYSTEM
14. USES
• ANTIBIOTIC MACROLIDES ARE USED TO TREAT INFECTIONS CAUSED BY ;
-GRAM-POSITIVE BACTERIA -STREPTOCOCCUS
-LIMITED GRAM-NEGATIVE BACTERIA -HAEMOPHILUS INFLUENZAE
- AND SOME RESPIRATORY TRACT AND SOFT-TISSUE INFECTIONS.
MACROLIDES ARE A COMMON SUBSTITUTE FOR PATIENTS WITH A
PENICILLIN ALLERGY.
BETA-HEMOLYTIC STREPTOCOCCI, PNEUMOCOCCI, STAPHYLOCOCCI, AND
ENTEROCOCCI ARE USUALLY SUSCEPTIBLE TO MACROLIDES.
15. UNLIKE PENICILLIN,
• MACROLIDES HAVE BEEN SHOWN TO BE EFFECTIVE AGAINST
LEGIONELLA PNEUMOPHILA, MYCOPLASMA, MYCOBACTERIA,
SOME RICKETTSIA, AND CHLAMYDIA
• MACROLIDES CAN BE ADMINISTERED IN A VARIETY OF WAYS THAT
INCLUDE TABLETS, CAPSULES, SUSPENSIONS, INJECTINGS AND
TOPICALLY.
16. DRUG INTERACTION
• 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.
• COLCHICINE IS A MEDICATION USED TO TREAT GOUT AND
BEHÇET'S DISEASE.
17. • ERYTHROMYCIN METABOLITES CAN INHIBIT CYTOCHROME P450
ENZYMES AND THUS INCREASE THE SERUM CONCENTRATIONS OF
NUMEROUS DRUGS INCLUDING,
• THEOPHYLLINE,
• ORAL ANTICOAGULANTS
• CYCLOSPORINE AND
• METHYLPREDNISOLONE
19. ERYTHROMYCIN
•
1st macrolide obtained from
Streptomyces erytherus in 1952
Active against gram + bacteria
Plasma half life- 2 hrs
Dose – adult (250-500mg 6 hourly)
Unstable in stomach acid
Formulated as enteric coated tablet
Used to treat upper respiratory tract infections
caused by streptococcus and haemophilus sp
like tonsillitis, pharyngitis, whooping cough
Used to treat chlamydial infections
To treat listerosis caused by listeria
Soft tissues infections
Pelvic inflammatory disease
Urethritis
Pneumonia
Gonorrhoea
Acne vulgaris
Rarely used to treat because of resistance and
alternative’s presence.
20. OPHTHALMIC USE OF ERYTHROMYCIN
• TREATING BACTERIAL INFECTIONS OF EYE
• PREVENT BACTERIAL INFECTION IN NEW BORN BABIES
• MEMBRANOUS CONJUNCTIVITIS – OINTMENT AT BEDTIME 0.5 %
• OPHTHALMIA NEONATORUM
21. CLARITHROMYCIN
Derived from erythromycin by
addition of methyl group
Active against both gram + and
gram – bacteria
More active against
Mycobacterium avium complex
(MAC)
Plasma half life – 6 hrs
Dose- 250-500 mg twice daily for
7 days
Respiratory tract and sinus infections
Treatment of infection by haemophilus,
MAC,H. Pylori in triple theray
Bacterial eye infections
22. AZITHROMYCIN
AZALIDE derived from
erythromycin by addition of
methylated nitrogen to lactone ring
Best activity against gram – bacteria
Half life > 2 days
Dose ; 250 -500 mg once daily for
4-7 days
HIGHER EFFICACY , LESSER
SIDE EFFECTS
Respiratory tract infections
Skin infections
STIs (Chlamydia, GC, chancroid)
Traveler's diarrhea
Mycobacterium avium complex (MAC)
Bacterial eye infections
23. OPHTHALMIA NEONAT0RUM
• CAUSED BY -GONOCOCCAL INFECTIONS (RARENOWDAYS)
- CHLAMYDIA OCULOGENITALIS
IN GONOCOCCAL HYPERACTUTE PURULENT CONJUNCTIVITIS
IN CHLAMYDIAL PAPILLARY REACTION WITHOUT FOLLICULAR
RESPONSE
IN CURATIVE TREATMENT OF CHLAMYDIAL INFECTIONS
SYSTEMIC ERYTHROMYCIN 50 MG / KG IN FOUR DIVIDED DOSES
FOR 3 WEEKS
