Brief Pharmacology of macrolide antibiotics

1. DR LINUS WAFULA,
JKUAT
MACROLIDES
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2. MACROLIDES
 ERYTHROMYCIN
 CLARITHROMYCIN
 ROXITHROMYCIN
 AZITHROMYCIN
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3. MACROLIDES
 Macrolide antibiotics contain a many membered lactone ring known as
macrocyclic ring to which one or more deoxy-sugars are attached.
• They are:
• Erythromycin
• Clarithromycin
Roxithromycin
• Azithromycin
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5.  Erythromycin is the first member of this group, and was isolated from a strain of
Streptomyces erythreus in 1952.
• Clarithromycin, Roxithromycin and Azithromycin are semi-synthetic derivatives of
erythromycin and these are also called newer macrolides.
• Some other macrolides are dirithromycin, oleandomycin and troleandomycin.
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6. Mechanism of action.
• Macrolide antibiotics are bacteriostatic agents and inhibit the protein synthesis
by binding reversibly to 50s ribosomal subunit of sensitive micro-organism and
interferes with ‘translocation’ step in the protein synthesis.
• The Gram-positive bacteria accumulate about 100 times more erythromycin than
the Gram-negative bacteria, hence G+ve bacteria are more sensitive than the G-ve
ones.
• Macrolides behave as bactericidal at very high concentrations.
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9. Bacteriostatic effect at low concentration and
bactericidal at high concentrations
Antimicrobial spectrum .
 These antibiotics are more active against G+ve cocci and inactive against most
of the aerobic and enteric G-ve bacilli.
• Also chlamydia, mycoplasma, spirochetes and toxoplasma
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10. Mechanism of Resistance
 Post-transcriptional methylation of the 23S bacterial ribosomal RNA.
 This acquired resistance can be either plasmid- mediated or chromosomal.
cross-resistance to macrolides do occur.
 Due to production of drug-inactivating enzymes (esterase's or kinases)
production of active ATP-dependent efflux proteins that transport the drug
outside of the cell.
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11. Erythromycin Resistance mechanisms:
 Reduced permeability of the cell membrane or active efflux;
 Production enzymes that hydrolyze macrolides;
 Modification of the ribosomal binding site
 There is cross resistance between erythromycin and the other macrolides.
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12. Physical & Chemical properties.
 Water insoluble molecules.
 Occurs as crystalline powders.
 Stable in aqueous solutions at or bellow room temperature.
 Unstable in acidic conditions and forms internal cyclic ketal.
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13. Pharmacokinetics
• Absorption: • Destroyed by the gastric juice so better given as enteric coated
tablet or in stearate form.
• Distribution: • Distributed all over the body except in CSF
• Macrolides are concentrated in the phagocytes and therefore enhance phagocyte
killing of bacteria
• Metabolism: • Occurs in liver by zero order kinetics → So the half-life increases
with increased dose → Contra-indicated in hepatic dysfunction
• Excretion: • Mainly excreted through the bile
• Renal excretion is only 5%
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14. Adverse effects of macrolides.
 GI toxicity
 Erythromycin --Moderate to severe epigastric distress due to a direct
stimulation of gut motility
 Anorexia, nausea, vomiting, and diarrhea
 clarithromycin, azithromycin – lesser degree of GI upset
 Cardiac toxicity
 Cardiac arrythmias– QT prolongation, ventricular tacycardia Hepatotoxicity
Erythromycin long term use – cholestatic hepatitis Azithromycin, clarithromycin-
lesser degree
 Allergic reactions- fever, skin eruptions , Auditory impairment, tinnitus
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15. Macrolides Drug Interactions.
 Erythromycin and Clarithromycin ONLY– are inhibitors of cytochrome P 450
system in the liver; may increase concentrations of:
 Theophylline Digoxin, Disopyramide, Carbamazepine, Valproic acid,
Cyclosporine .
 Terfenadine,
 Astemizole
 Phenytoin
 Cisapride
 Warfarin
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16. 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, Clamidia,
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.
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18. Pharmacokinetics Erythromycin
 Absorption incomplete but adequate from intestine.
 Inactivated by gastric HCL, hence given as : Enteric coated tablets or ester
(stearate, ethyl succinate )
 Food delays absorption.
 Not metabolized and actively secreted in bile ( major route of excretion ).
 Only 2-5 % is excreted in active form in urine.
 Widely distributed into most tissues, except the brain and CSF.
 Cross the placental barrier.
 Protein binding – 70- 80 %
 Half – life approx. 1.5 hr.Half – life approx. 1.5 hr.
 Dose: 250-500mg/QID/oral
 Max dose. 4gm/daymax.
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21. Advantages of clarithromycin.
 Cannot undergo cyclic ketal formation, so doesn’t cause cramp in GI
 Higher blood concentrations.
 More lipophyl.
 Lower doses with less intervals.
Uses:
 Atypical mycobacterial infection
 Resistant leprosy
 Toxoplasmosis
 H.Pylori induced peptic ulcers
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24. Azithromycin Pharmacokinetics.
 Rapidly absorbed from GIT
 Food delays absorption
 Widely distributed ( extensive tissue distribution ), except CSF
 Protein binding 51%
 Undergo some hepatic metabolism ( inactive )
 Biliary route is the major route of elimination
 Only 6% is excreted unchanged in the urine
 Half- life approx. 2-4 days.
 Dose:Dose: 500mg/OD/oral500mg/OD/oral 10mg/kg/BD10mg/kg/BD Children
 Advantage over erythromycin & clarithromycin
 Once daily dosing
 No inhibition of cytochrome P- 450
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26. ROXITHROMYCIN
 Properties: Semi-synthetic 14–membered ring macrolide antibiotic in which the
erythronolide lactone ring has been altered to prevent inactivation in the
intestine.
Uses:
 Active against both gram (+) & gram (-).
 Treatment of skin ,dental & genital infections.
 Treatment of upper & lower respiratory tract infections.
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28. Macrolides Effect on Motilin receptors.
• Erythromycin stimulates motilin receptors in the GIT which induces gastric
contractions.
• This leads to early gastric emptying and increased intestinal motility without
significantly affecting the colonic motility.
• Due to this property, it is also used in
• diabetic gastroparesis and
• post operatively to promote the peristalsis in the cases of post-operative paralytic
ileus.
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29. Spiramycin.
• Spiramycin is also a macrolide antibiotic.
• It resembles erythromycin in spectrum of activity and properties. • Its specific
utility is for toxoplasmosis and recurrent abortions in pregnant women.
• It limits risk of transplacental transmission of Toxoplasma gondii infection.
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30.  It is given in a dose of 3 million units (MU) BD/TDS for 3 weeks. (Three week
course is to be repeated after 2 weeks gaps till delivery).
• Other indications are similar to erythromycin with a dose of 6 MU per day for 5
days.
• Common side effects are: • Gastric irritation, • Nausea, • Diarrhoea and • Rashes.
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31. Ketolies/ Ketolides
 Telithromycin,
 Cethromycin &
 Solithromycin
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32. Telithromycin
• It is a semi-synthetic derivative of erythromycin and also called as Ketolide, due
to a keto group in its structure.
• It blocks protein synthesis by binding to domains II and V of 23S ribosomal RNA
of the 50S ribosome subunit.
• It may also inhibit the assembly of nascent ribosomal units.
• Due to this changed structure, it is more active against the Macrolide resistant
G+ve micro- organisms.
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33.  It is given orally as once daily dosage schedule in a dose of 400 mg OD.
• The half-life is 10 hrs.
• Telithromycin is used as treatment of respiratory tract infections including:
• Acute exacerbation of chronic bronchitis,
• Acute bacterial sinusitis and
• Community acquired pneumonia.
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34. Side effects
 The major side effects are:
• Reversible hepatic dysfunction,
• Prolongation of QTc interval and
• Transient visual disturbances.
• Interactions: • Additive effect on QT interval prolongation w/ class 1A (e.g.
quinidine, procainamide) or class III (e.g. dofetilide) antiarrhythmic agents).
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35. Cethromycin.
• More potent than telithromycin
• Used against macrolide resistant Streptococci and Enterococci
Resistance:
• Ribosomal modification via inducible or constitutive methylation.
• Ribosomal modification via point mutation- H. pylori
• Drug efflux- S. pyogenes
• Adverse reactions • Diarrhoea, nausea
Drug interaction • Prolonged QT interval (cisapride, terfenadine) • Increased blood
levels of theophylline, midazolam.
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36. INDICATIONS
 Indicated in: • Community acquired pneumonia • Prevention of post exposure
inhalational anthrax • It is discovered as orphan drug. • Now under Phase III
clinical trial.
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37. Solithromycin.
 MOA: • Solithromycin inhibits bacterial translation by binding to the 23S
ribosomal RNA, preventing the offending bacteria from synthesizing proteins.
• Abs spectrum: • G+ve respiratory tract pathogens, macrolide-resistant strains.
• Indicated in Community acquired pneumonia. • M/C ADR: hepatotoxicity.
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38. Other indications of Macrolides.
 Diffuse pan-bronchiolitis
• Cystic fibrosis
• Acute bacterial sinusitis
• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Bronchiectasis
• Chronic bronchitis
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39. ASANTENI
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