Download pharmacology-lect-9-n-7-macrolide

Protein Synthesis Inhibitors
Dr. Naza M. Ali
9-1-2017
Lec-9
• These drugs selectively inhibit bacterial
protein synthesis.
• The selectivity is due to the differences
between bacterial and human ribosomal
proteins, RNA, and associated enzymes.
• Bacteria have 70S ribosomes with 50S and 30S
subunits
• Mammalian cells have 80S ribosomes with 60S
and 40S subunits.
Classification of some antibacterial agents by their sites of action
Macrolides
 The macrolides are a group of antibiotics
with a Large cyclic lactone structure to which
one or more deoxy sugars are attached.
Macrolides
-Erythromycin
125mg , 250mg, 500mg
-Clarithromycin
500mg
-Azithromycin
200mg, 250 mg, 500mg
-Roxithromycin
150mg, 500mg
-Spiramycin
1,500,000 IU
3,000,000 IU
Mechanism of action
• Macrolides bind irreversibly to a site on the
50S subunit of the bacterial ribosome,
inhibiting the translocation steps of protein
synthesis.
• Also interfere with transpeptidation steps.
• Bacteriostatic, or bactericidal higher doses
Antibacterial spectrum
Erythromycin:
-is effective against many of the same organisms
as penicillin G
-it is used in patients who are allergic to the
penicillins (syphilis)
- It is used in Corynebacterium Diphtheriae
Clarithromycin:
-Same of erythromycin, active H.influenzae
-Its has higher activity than that of erythromycin
against
Chlamydia,
Legionella,
Moraxella,
H. pylori
Azithromycin:
-less active against strepto & staphyl than erythromycin
-more active against respiratory infections due to
H.influenzae , Moraxella catarrhalis.
-preferred therapy for urethritis due to Chlamydia
trachomatis (single dose).
-Community acquired pneumonia (4 day course )
Resistance
1) The inability of the organism to take up the antibiotic
or the presence of an efflux pump, both of which limit
the amount of intracellular drug.
2) A decreased affinity of the 50S ribosomal subunit for
the antibiotic.
3) The presence of a plasmid-associated erythromycin
esterase.
Pharmacokinetic:
Absorption
• The erythromycin base is destroyed by gastric acid
So, either enteric-coated tablets
or esterified forms of the antibiotic are administered.
• All are adequately absorbed upon oral administration
Clarithromycin, azithromycin, and telithromycin are
stable to stomach acid and are readily absorbed.
• Food interferes with the absorption of erythromycin &
azithromycin, but can increase that of clarithromycin.
Distribution:
• Erythromycin distributes well to all body fluids
except CSF.
• It is one of the few antibiotics that diffuses into
prostatic fluid, and it also accumulates in
macrophages.
• Clarithromycin, azithromycin are widely distributed
in the tissues.
• Azithromycin concentrates in neutrophils,
macrophages, and fibroblasts.
• Azithromycin concentration in phagocyte
lysosomes can be 40 times higher than in blood and
they can enhanced intracellular killing of bacteria by
phagocytes
• Inflammation allows for greater tissue penetration.
• It has the longest half-life and the higher volume of
distribution
Pharmacokinetics
Elimination:
• Erythromycin and telithromycin are extensively
metabolized hepatically.
• They inhibit the oxidation of a number of drugs
through their interaction with the CYP450 system.
Excretion:
• Erythromycin and azithromycin are primarily
concentrated and excreted in the bile as active
drugs.
• Partial reabsorption occurs through the
enterohepatic circulation.
• Clarithromycin and its metabolites are
eliminated by the kidney as well as the liver.
• The dosage of this drug should be adjusted in
patients with renal impairment.
Excretion
Adverse effects
1. GIT irritation
2. Cholestatic jaundice: ( erythromycin estolate form)
3. Ototoxicity: transient deafness at high dosage
 Contraindication:
Patients with hepatic dysfunction should be treated
with caution, because these drugs accumulate in the
liver.
Interactions:
-Erythromycin, telithromycin, clarithromycin inhibit
hepatic metabolism of a number of drugs, lead to
toxic accumulations of these compounds.
Telithromycin
-Is a ketolide structurally related to macrolides.
-same mechanism of action as erythromycin & a
similar spectrum of antimicrobial activity.
-some macrolide–resistant strains are susceptible
to telithromycin.
Clinical use:
Community acquired pneumonia,
other upper respiratory tract infections.
Telithromycin is given orally once daily.
Fidaxomicin
• Is a macrocyclic antibiotic with a structure similar to
the macrolides;
Mechansim of action
• it has a unique mechanism of action.
-acts on the sigma subunit of RNA polymerase,
-thereby disrupting bacterial transcription,
- terminating protein synthesis,
-and resulting in cell death in susceptible organisms.
• Fidaxomicin has a very narrow spectrum of activity
limited to gram-positive aerobes and anaerobes.
• it possesses activity against staphylococci and
enterococci
• It is used primarily against Clostridium difficile.
• Following oral administration, has minimal systemic
absorption and primarily remains within GIT .
• This is ideal for the treatment of C. difficile infection,
which occurs in the gut.
• This characteristic also likely contributes to the low
rate of adverse effects.
• Hypersensitivity reactions may occur.
• Fidaxomicin should be used with caution in patients
with a macrolide allergy, as they may be at increased
risk for hypersensitivity.