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O
H3C
CH3
H3C
OH
HO
CH3
H3C
HO
N
OH
H3C
O
O
O
CH3
CH3
O
O
CH3
O
O
CH3
H3C
CH3
Erythromycin
OH
CH3
• 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
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.
• 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.
Mechanism of action
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
PHARMACOKINETICS
• 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
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)
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).
INTERACTIONS
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
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:
1.
2.
3.
4.
Campylobactor enteritis
Legionnaire’s pneumonia
Chlamydia trachomitis
Pencillin resistant Staphylococcal infections
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
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 t1/2 - 12 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.
ROXITHROMYCIN
CLARITHROMYCIN
O
H3C
CH3
9
CH3
O
HO
CH3
CH3
H3C
OH
12
H3C
N
6
HO
5
H3C
O
O
O
1
1`
3
O
O
OH
CH3
1``
CH3
OH
O
Clarithromycin
CH3
CH3
CH3
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
INDICATIONS
•
•
•
•
•
•
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.
AZITHROMYCIN
H3C
N
CH3
H3C
OH
HO
CH3
CH3
12
H3C
OH
N
HO
5
H3C
O
O
O
1
CH3
1`
3
O
O
CH3
OCH3
1``
CH3
OH
O
Azithromycin
CH3
CH3
CH3
AZITHROMYCIN
• 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%
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.
THANK YOU
- PHARMA STREET