Pharmacology

1. Dr.Zulcaif Ahmad

2. Macrolides
 History
 Chemistry
 Classification
 Mechanism of Action
 Antibacterial Spectrum
 Bacterial Resistance
 Pharmacokinetics
 Adverse Effects

3. Introduction
O
O O
O
CH3
HO
H3C
CH3
CH3
O
H3C
H3C
O
HO
CH3
N CH3
H3C
Picromycin
The term Macrolide was originally given to antibiotics
produced by species of Streptomyces.
In 1950 the first drug of this class was isolated: Picromycin
In 1952 Erythromycin and Carbomycin were introduced into
clinic.

4. General Structure
O
O
O
CH3
R1
H3C
CH3
CH3
O
H3C
OH
H3C
CH3
OH
O
O
HO
CH3
N
CH3
CH3
O OH
CH3
CH3
OR2
1 3
5
9
12
1`
1``
Erythromycin
Glycon
Aglycone
They all contain three characteristics parts in the molecule:
 A highly substituted macrocyclic lactone: aglycone.
 A ketone group.
 An amino desoxysugar: glycon, and in some of the macrolides, a
neutral desoxysugar which are glycosisically attached to the
aglycone ring.

5. The lactone ring usually has 12, 14, or 16 atoms and is
often unsaturated
macrolide antibiotics are weak bases and different
salts with pKa range of 6.0-9.0 can be formed on the
amino group.
Macrolides are water-insoluble molecules. Salts
prepared by glucoheptonic and lactobionic salts are
water soluble, whereas stearic acid and laurylsulfuric
acid salts are water-insoluble.
Macrolides are stable in aqueous solutions at or below
room temperature. They are unstable in acidic or basic
conditions or at high temperatures.

6. It has been the subject of chemical manipulations to:
a) Increase the water solubility of the drug for
parenteral dosage forms.
b) Increase the lipid solubility and hence chemical
stability of the drug against aqueous acidic
conditions as well as increase in oral absorption and
masking the bitter taste of the drug.

7. Chemical Instability of Macrolide Antibiotics
O
O
CH3
CH3
O
H3C
CH3
O
O
CH3
1 3
12 6
89
O
H3C
HO
H3C
Anhydroerythromycin
6,9;9,12-spiroketal
O OH
CH3
CH3
OR2
1``
O
HO
CH3
N
CH3
CH3
1`
 Macrolides are unstable under acidic conditions and
undergo an intramolecular reaction to form an
inactive cyclic ketal.

8. Chemical Instability..
The cyclic ketal is the cause of intestinal cramp
which is reported after the use of erythromycin.
Water-insoluble salts and enteric coated dosage
forms of macrolides have less such a side effect.
Water insoluble forms cannot take part in the
reactions which occur in aqueous solutions.
Stearate salt is an example of insoluble salts of
erytromycin.

9. Classification
Macrolides
 Erythromycin
 Clarithromycin
 Azithromycin
 Dirithromycin
 Telithromycin
 Oleandomycin
 Tylosin
 Spiramycin

10. Lincosamides
Lincomycin
Clindamycin

11. Mechanism of Action
 Macrolides attach to the 50s portion of bacterial
ribosomes and inhibit the protein synthesis.
 Prevent translocation during elongation of protein
synthesis
 Their binding site is either identical or in close
proximity to that for clindamycin and chloramphenicol.

12. Mechanism of action of erythromycin and clindamycin.

13. Spectrum of Antibacterial Activity
Macrolides are similar to penicillins regarding their
spectrum of activity.
They are effective against penicillin-resistant strains.
Macrolides are effective against most of the G(+)
bacteria, cocci or bacillus, they have antibiotic
activity against G(-) cocci ,especially Neisseria Spp
too.
Macrolide antibiotics are effective against
Mycoplasma, Chlamydia, Campylobacter and
Legionella in contrast to penicillins.
They are less effective against G(-) bacteria, though
some strains of H. influenza and Brucella are
sensitive to the antibacterial activity of this class of
antibiotics.

14. Typical therapeutic applications of macrolides.

15. Bacterial Resistance
 Methylation of a guanine residue on ribosomal RNA leads
to lower affinity toward macrolides
 An active efflux system
 presence of a plasmid-associated erythromycin esterase.
 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.

16. Pharmacokinetics
 Absorption: Enteric coated preparations protect the
antibiotic from gastric acid destruction allowing oral
absorption
Also when stable esterified salts are used.
 Fate: Widely distributed to all tissues except CNS.
 Excretion: Metabolized by liver and excreted by bile .
 Tylosin and telmicosin excreted unchanged in bile and
urine.

17. Administration and fate of the macrolide antibiotics.

18. Some properties of the macrolide antibiotics.

19. Inhibition of the cytochrome P450 system by erythromycin,
clarithromycin, and telithromycin.

20. Adverse Effects
 Epigastric distress: Common with erythromycin
 Cholestatic jaundice: Especially with the estolate form of
erythromycin
 Ototoxicity: Transient deafness associated with
erythromycin, at high dosages.
 Contraindications: Patients with hepatic dysfunction.
 Interactions: Inhibit the hepatic metabolism of a number
of drugs

21. Some adverse effects of macrolide antibiotics.

22. Clinical Application
of Erythromycin
It is used to treat
The upper part of the respiratory tract infections,
Soft tissue G(+) infections,
Mycoplasma pneumonia caused pneumonia,
Campylobacter jejuni enteritis,
Chlamydia infections.
Gonorrhoea.
It is a good choice for penicillin-sensitive cases.

23. Clarithromycin
O
O
O
CH3
HO
H3C
CH3
CH3
O
H3C
OH
H3C
O
O
O
HO
CH3
N
CH3
CH3
O OH
CH3
CH3
OH
1 3
5
9
12
1`
1``
Clarithromycin
H3C
CH3
6
 6-Methyl ether of erythromycin.
 Cannot undergo cyclic ketal formation, so doesn’t cause cramp in
GI.
 Higher blood concentrations.
 More lipophyl.
 Lower doses with less intervals.

24. Azithromycin
O
O
CH3
HO
H3C
CH3
O
H3C
OH
CH3
OH
O
O
HO
CH3
N
CH3
CH3
O OH
CH3
CH3
OCH3
1 3
5
12
1`
1``
N
CH3
H3C
H3C
Azithromycin
 Azalide, a semisynthetic macrolide with a15 membered ring.
 Stable under acidic conditions, because it doesn’t form cyclic
ketal.
 In the treatment of urogenital infections caused by N.
gonorrhoeae and Chlamidia trachomatis.
 Longer half-life.

25. Oleandomycin
O
O
O
CH3
H3C
CH3
O
H3C
OH
H3C
H3C
O
O
RO
CH3
N
CH3
CH3
O OR
CH3
1 3
5
9
12
1`
1``
Oleandomycin, R=H
Troleandomycin R=COCH3
6
O
O
CH3
 Oleandomycin is isolated from Streptomyces antibuticus.
 Bacteriostatic effects the same as erythromycin.

26. Lincosamide
 First lincosamide to be discovered is lincomycin, isolated from
Streptomyces lincolnensis
 Lincosamides are derivatives of an amino acid and a sulfur-
containing octose.
 Lincosamides, macrolides, and chloramphenicol, although not
structurally related, seem to act at this same site.
 The lincosamides are bacteriostatic or bactericidal depending on
the concentration.
 Activity is enhanced at an alkaline pH.
 Lincomycin has been superseded by clindamycin, which exhibits
improved antibacterial activity.

27. Clindamycin
 Mechanism same as that of erythromycin
 Good for anaerobic organisms (Bacteroids)
 Resistance like erythromycin
 Well absorbed by the oral route.
 It distributes well into all body fluids except the CSF.
 Penetration into bone occurs even in the absence of
inflammation.
 The drug is excreted into the bile or urine .
Adverse effect:
 In addition to skin rashes, serious adverse effect is fatal
pseudomembranous colitis caused by C. difficile, which is
treated by metronidazole or vancomycin .

28. Administration and fate of clindamycin.

29. Ketolides
 Ketolides are antibiotics belonging to the macrolides
group.
 Ketolides are derived from erythromycin by
substituting the cladinose sugar with a keto-group and
attaching a cyclic carbamate group in the lactone ring.
 These modifications give ketolides much broader
spectrum than other macrolides.

32.  Ketolides are effective against macrolide-resistant
bacteria as well as having a structural modification
that makes them poor substrates for efflux-pump
mediated resistance.
 Ketolides block protein synthesis by binding to
ribosomal subunits and may also inhibit the formation
of newly forming ribosomes.
 The only ketolide on the market at this moment is
Telithromycin, which is sold under the brand name
of Ketek.
 Other ketolides in development include Cethromycin
and Solithromycin.