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 PROTEIN SYNTHESIS INHIBITORS

 AMINOGLYCOSIDES
 TRETRACYCLINES
 CHLORAMPHENICAL
 MACROLIDES

PROF: DR:MANZOOR AHMED UNAR

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 AMINOGLYCOSIDES
It is a group of antibiotics, used most widely
against aerobic Gram negative microorganisms.
Streptomycin, Gentamicin, Neomycin, Netilmicin,
Tobramycin, Kanamycin, Sisomicin, Amikacin,
Paromomycin

Derived from Streptomyces are named with the suffix – mycin

Derived from Micromonospora are named with suffix –micin.

“-y-” : from Streptomyces (e.g. tobramycin)

“-I-” : from micromonospora (e.g. gentamicin)
“-kacin” : from kanamycin (e.g. amikacin)
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 AMINOGLYCOSIDES
Classification on the bases of their side effects

1. Causing Cochlear Nerve Damage:

Kanamycin, Amikacin, Netilmicin, Neomycin.

2. Causing Vestibular Nerve Damage:

Gentamicin, Tobramycin, Streptomycin .

3. Causing Nephrotoxicity:
Gentamicin, Tobramycin, Neomycin.

4. Which Are Not Given Parenterally:

Neomycin.

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Mechanism Of Action of AMINOGLYCOSIDES

By passive diffusion, than actively transported

across the cell membrane, into cytoplasm by an
oxygen- dependent process.
By binding to bacterial 30-S ribosome, inhibit
protein synthesis irreversible by three steps:

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 Mechanism Of Action of AMINOGLYCOSIDES

(i). Block the formation of the initiation complex,

(Inhibiting the translocation of tRNA from site-A to site-P)

(ii). Inducing misreading of mRNA, which causes

incorporation of incorrect amino acid into peptide
and results in non-functional or toxic protein.
(iii). Break up of
polysomes into
non-functional
monosomes.

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 AMINOGLYCOSIDES
Resistance

1. Inactivation of Aminoglycosides by transferase

enzymes produced by microorganism:
AAC ( acetyl-transferase ) acetylation
ANT ( adenyl-tranferase ) adenylylation
APH ( phospho-transferase ) phosphorylation

2. Impaired entry of Aminoglycoside into cell:

Mutation or deletion of porin protein, or
nonfunctional oxygen dependent transport process.

3. Alteration in ribosome receptor:

Receptor protein on the 30-S ribosome may be
deleted or altered as a result of mutation.
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 AMINOGLYCOSIDES
Pharmacokinetics
 Absorbed very poorly from the intact GIT,
 Only Neomycin can be used orally.
 Half-life: 2 – 3 hours ( 24 – 48 hours in renal failure )
 Excreted by the kidneys & excretion is directly
proportional to creatinine clearance.

If creatinin clearance is 100ml/min, gentamicin is given 5mg/kg,

If creatinin clearance is 80ml/min; gentamicin is given 4mg/kg
If creatinin clearance is 50ml/min; gentamicin is given 3mg/kg
If creatinin clearance is< 50ml/min; gentamicin is given 2mg/kg

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 Spectrum of Activity of AMINOGLYCOSIDES
 Have concentration-depending killing property,
 They have significant Post Antibiotic Effect.
 They are bactericidal, effective against aerobic Gram
negative bacteria, (Pseudomonas & Enterobacter).
 Used in septicemia & GIT, UTI, respiratory tract.
 Mycobacteria are susceptible to streptomycin,
amikacin.
 Paramomycin is used against parasitic infection.
 For streptococcal infection (endocarditis), they give
synergistic effects with β-lactam antibiotics
( pen & gent ) ( amp & gent ). 11
 Clinical uses of AMINOGLYCOSIDES

Streptomycin:
 Mycobacterial Infections: First-line treatment of TB.

 Non- Mycobacterial Infections: Pseudomonas, Enterococcal

endocarditis, Plague, Tularemia, Brucellosis, Proteus,
Enterobacter, Klebsiella.

Gentamicin:
 Topical administration: creams, ointment, solutions
for burns, wounds.
 Intrathecal administration: for meningitis by G-ve.

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 Clinical uses of AMINOGLYCOSIDES
 Tobramycin: more active against Pseudomonas.
 Amikacin: Many gram negative enteric bacteria (pseudomonas )
and strains of multi drug resistant Mycobacterium are
susceptible to Amikacin.
 Neomycin is too toxic for parenteral use.
Used topically, Orally for bowel surgery.
For hepatic coma to reduce ammonia intoxication.
 Paromomycin: orally, intestinal amoebiasis.
Kanamycin , can cause curare-like neuromuscular
blockade & respiratory arrest.
( calcium gluconate & neostigmine act as antidotes )

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 Side Effects of AMINOGLYCOSIDES

 All Aminoglycosides are ototoxic & nephrotoxic.

loop diuretics can potentiate nephrotoxicity.

 Cochlear nerve damage: tinnitus & hearing loss.

 Vestibular damage: ataxia & vertigo.
 Allergic reactions on topical use of neomycin & gent:
 Curare-like neuromuscular blockade.

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 Precautions for AMINOGLYCOSIDES
 Pre-existing medical conditions—such as
Kidney disease, Eighth cranial nerve disease,
Myasthenia gravis, Parkinson’s disease should be
discussed prior to taking any Aminoglycoside.
 Pregnant women are usually
not advised Aminoglycosides,
because they can damage to
infant’s hearing, kidneys, or
sense of balance.
 Aminoglycosides not pass into breast milk .
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 TETRACYCLINES

 Tetracyclines are a large family of antibiotics with a

common activity & basic structure ( four fused rings ).
 Chlortetracycline,
 Oxytetracycline,
 Teracycline,
 Demeclocycline,
 Glycyclines (synthetic),
 Doxycycline,
 Minocycline.

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 Pharmacokinetics of TETRACYCLINES

 Used orally, i/v, i/m

 Absorption occurs in the upper small intestine,
 Absorption impaired (except doxycycline &
minocycline ) by food, divalent cations (Ca +2, Mg+2,
Fe+2) or Al+3, dairy products, antacids & alkaline pH.
 Specially buffered tetracycline solutions are
formulated for intravenous administration.

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 Mechanism of action of TETRACYCLINES

 They inhibit protein synthesis.

 Enter the microorganism by passive diffusion &
active transport.
 Inhibit the binding of aminoacyl - tRNA to the
30-S ribosomal subunit in the bacteria.
 Prevent addition of amino acid to the growing protein.
 Binding is reversible.

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 Antimicrobial activity of TETRACYCLINES
 They are broad-spectrum, bacteriostatic antibiotics,
for Gram - positive & Gram - negative bacteria,
(anaerobes, rickettsiae, chlamydiae, mycoplasmas)

 Also active against some protozoa (amebiasis).

 Glycyclines are active against both

tetracycline susceptible & tetracycline resistant
aerobic & anaerobic Gram+ve & Gram-ve bacteria.

 Tigecycline is a new, active against

methicillin-resistant Staphylococcus aureus.
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 Resistance to TETRACYCLINES

 Impaired influx or increased efflux .

 Enzymatic inactivation .
 Ribosome protection, interfere with tetracycline
binding to the ribosome.

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 Indications of TETRACYCLINES
 Tetracycline is the drug of choice in infections with
Mycoplasma chlamydiae, rickettiae & spirochetes.

 Used for Helicobactor pylori, Protozoal infection.

 Used for Gram+ve & Gram-ve bacterial infections,
 Sexual transmitted disease ,
 Acne, bronchitis, pneumonia, UTI, TB.
 With aminoglycosides for plague, tularemia,
brucellosis.

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 TETRACYCLINES

Tetracyclines also have non-antibiotic properties

include:
 Anti-inflammatory effects,

 Inhibition of metalloproteinase ,

(enzymes that inhibit collagen & gelatin production)

 Reduce new blood vessel formation (angiogenesis).

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 Side effects of TETRACYCLINES
 Nausea, vomiting, diarrhea, Super infections.
 Dizziness, vertigo.
 Photosensitivity, ( Demeclocycline) induce sensitivity to sunlight in
fair-skinned persons.
 Yeast infection in female genital (vaginal itching & discharge)
 Teeth in the growing children, causes discoloration of
the teeth & emamel dysplasia.
 Bone deformity, growth inhibition.
 Liver Toxicity: especially in Pregnant women.
 Kidney Toxicity:

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 TETRACYCLINES
Precautions / Contraindications

 Pregnancy,
 Breast-feeding women,
 Children under twelve years,
 Tetracycline should not be taken at mealtime,
 Tetracycline should not be taken with antacids or iron,
 Outdated medicine not be taken (causes kidney damage),
 Tetracycline reduce the efficacy of the oral contraceptives,
 If unexpected sunburn occur, take the medicine in the evening.

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 CHLORAMPHENICOL

 It was isolated in 1947 from cultures of

“Streptomyces venezuelae” & Synthesized in 1949.
 Soluble in alcohol, neutral & stable compound.
 Widely distributed to all tissues & body fluids.

Excretion: active form (10%) & inactive (90%) by

urine & by bile or feces.

 Chloramphenicol crystalline used orally,

 Chloramphenicol palmitate is a prodrug,
 Chloramphenicol succinate used parentral,
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 Mechanism of action of CHLORAMPHENICOL

 Potent inhibitor of microbial protein synthesis.

 It binds reversibly to the 50-s subunit of bacterial
ribosome.
 Block the formation of peptide bond by inhibiting
peptidyl transferase activity.

Resistance:
 Due to production of acetyl transferase,
(a plasmid encoded enzyme that inactivates the drug)

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 Antimicrobial activity of CHLORAMPHENICOL
 It is a bacteriostatic, broad spectrum antibiotic.
 Active against both aerobic & anaerobic
Gram-positive & Gram-negative organisms.
 It is also active against Rickettsiae.
 Chloramphenicol may be bactericidal for
Haemophilos influenza, Neisseria meningitis.
 Streptococci, Pneumoniae, Haemophilus Influenzae
 Neisseria. Meningitidis, Salmonillae Typhi
 Esccherichio. Coli, Vibro Cholera,
 Ricketsiae , Anaerobes- Clostridium.
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 Clinical Uses 0f CHLORAMPHENICOL

 Used for serious infections for which other

antibiotics are either ineffective or contraindicated.

 Due to potential toxicity, bacterial resistance & the

availability of other effective drugs, it’s use is limited.

 Typhoid fever- S. typhi (quinolones are preferred )

 Meningitis – N.meningitidis (Ceftriaxone is preffered )
 Rickettsial infections – ( Doxycycline is preferred )
 Bacterial conjunctivitis ( topical / eye ointment).

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 Adverse Reactions Of CHLORAMPHENICOL

 Gastrointestinal disturbance.
 Oral & vaginal candidacies.
 Bone marrow depression leads to Aplastic anemia .
 Idiosyncratic reaction, irreversible, can be fatal.
 Gray baby syndrome: Neonates have low capacity
to glucuronidate the antibiotic & have undeveloped
renal function, so decreased ability to degrade &
excrete the drug, which accumulates and causes
Gray baby syndrome (vomiting, hypothermia,
gray color, cyanosis, depressed breathing,
cardiovascular collapse & death).
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 Drug interactions CHLORAMPHENICOL

 Inhibits microsomal enzymes, so serum conc: of

Phenytoin, Tolbutamide, & Warfarin are increased .
 Chloramphenicol can antagonize bactericidal drugs,
such as Penicillins or Aminoglycosides.

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 MACROLIDES

 Macrolides are a group of closely related compounds

characterized by a macrocyclic lactone ring.
 Erythromycin is prototype drug was obtained in 1952
from Streptomyces erythreus.
 Clarithromycin & Azithromycin are semisythetic.
 Ketolides & Telithromycin are semisythetic.
 Destroyed by stomach, used enteric coated.
 Excreted by bile, feces,& urine.

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 Mechanism of action of ERYTHROMYCIN

 Inhibition of protein synthesis via

binding to 50-S ribosomal RNA,
which blocks the aminoacyl
translocation & formation of
initial complex.

 Effective against gram-positive, pneumococci,

streptococci, staphylococci, corynebacteria.
Mycobacterium kansasi & scrofulaceum .
Gram-negative Neisseria, Bordetella, Bartonella ,
Treponema pallidum & campylobacter.
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 ERYTHROMYCIN
Indication:
 Drug of choice for corynebacterial infection, Diphtheria.
 First line agent for pharyngitis, skin, soft tissue.
 Respiratory tract infection.
 Genital chlamydial infection.
 Community-acquired pneumonia.

 Clarithromycin: Also activity against H.influenza,

Mycobacterium leprae, Toxoplasma gondii.
 Azithromycin: Also active against M. leprae, T.gondii.

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 ERYTHROMYCIN

Resistance:
 Reduce permeability,
 Active efflux,
 Production of esterases that hydrolyze Macrolides.
 Modification of ribosomal binding site (Protection).

Adverse reactions:
 Anorexia, nausea, vomiting, diarrhea are common.
 Acute cholestatic hepatitis, fever, rashes.
 Inhibit P450 enzymes (warfarin, cyclosporin).

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