Transcript Protein Synthesis Inhibitors

Protein Synthesis
Inhibitors
BY
S.Bohlooli, PhD
School of Medicine, Ardabil University of Medical Sciences
Protein Synthesis Inhibitors
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Tetracyclines
Amimoglycosides
Macrolides
Clindamycin
Chloramphenicol
Streptogramines
Oxazolidinones
Tetracycline
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First compound, chlortetracycline
introduced in 1948
Highly effective against rickettsiae, gm +
and – bacteria, chlamydia
Inhibit protein synthesis by reversibly
binding to 30 S subunit of bacterial
ribosome, preventing binding of aminoacyl
tRNA to mRNA ribosomal complex
Bacteriostatic
Chemical Structure
Chemical Structure
Inhibition of bacterial protein synthesis by tetracyclines.
Resistance
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Wide resistance limits clinical uses
Most penicillinase-producing staphylococci
are resistant
Absorption
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Incomplete GI absorption: tetracycline (6080%), doxycycline (95%), minocycline
(100%)
Dairy foods decrease absorption by forming
nonabsorbable chelates with calcium ions; also
Mg, Fe, Al (antacids)
Distribution
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Widely distributed in body
Bind in tissues undergoing calcification (teeth,
bones) or tumors with high calcium content
(gastric carcinoma)
All cross placenta and concentrate in fetal
bones and teeth
Minocycline best CSF penetration
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Concentrated in saliva and gingival fluid
Excretion
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Concentrate in liver and partially metabolized
Secreted into bile and excreted in urine
Doxycycline and minocycline largely excreted
in feces
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Use in renal insufficiency
General Therapeutic Uses
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Lyme disease
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Mycoplasma pneumonia
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Young adult pneumonia
Rocky mountain spotted fever
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Spirochete (Borelia burgdorferi) tick bite
Skin lesions, headache, fever,
meningioencephalitis, arthritis
Fever, chills, bone and joint aches
Acne
General Therapeutic Uses
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Chlamydia
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Lymphogranuloma venereum- lymph node
hypertrophy, obstruction, elephantiasis
Psittacosis- pneumonia, hepatitis, myocarditis,
coma
Cholera
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Ingested fecally contaminated food or water
Organism multiplies in GI tract and secretes
enterotoxin producing diarrhea
Doxycycline reduces organism
Fluid replacement
Adverse Effects
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GI discomfort
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Hepatic injury
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Anorexia, epigastric pain, abdominal distention,
nausea, vomiting, diarrhea, sore mouth, perianal
irritation
Increased during pregnancy
Nephrotoxicity
Adverse Effects
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Teeth
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Depression of bone growth
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Deposition in fetal and growing bones, stunted growth
Photosensitization
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Discoloration enamel and hypoplasia of teeth
Severe sunburn in sun; doxy/demeclocycline
Superinfections
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Candida or GI staphylococcus
Contraindications
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Pregnancy
Children
Renal insufficiency
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Can use doxycycline
Drug Interactions
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Do not give with other antibiotics unless
establish synergy
Increased effects of anticoagulants
Not absorbed by cations like Ca, Mg, Fe, Al
H2 blockers may depress tetracycline uptake
Aminoglycosides
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Contain amino sugars linked to
aminocyclitol by glycosidic bonds
Binds to 30 S ribosomal subunit
(streptomycin) or 50 S (gent/others),
interfering with assembly of functional
ribosomal apparatus or misreading of
genetic code
Aerobic gram negative bacteria
Bactericidal or static
Typical Minimal Inhibitory Concentrations of Aminoglycosides That Will Inhibit 90%
(MIC90) of Clinical Isolates for Several Species
MIC90, mg/ml
SPECIES
KANAMYCIN
GENTAMICIN
NETILMICIN
TOBRAMYCIN
AMIKACIN
Citrobacter freundii
8
0.5
0.25
0.5
1
Enterobacter spp.
4
0.5
0.25
0.5
1
Escherichia coli
16
0.5
0.25
0.5
1
Klebsiella pneumoniae
32
0.5
0.25
1
1
Proteus mirabilis
8
4
4
0.5
2
Providencia stuartii
128
8
16
4
2
Pseudomonas
aeruginosa
>128
8
32
4
2
Serratia spp.
>64
4
16
16
8
Enterococcus faecalis
æ
32
2
32
≥ 64
Staphylococcus aureus
2
0.5
0.25
0.25
16
* Adapted from Wiedemann, B., and Atkinson, B.A., 1991.
Resistance
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Decreased uptake
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Altered receptor
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Absent oxygen-dependent transport
30S ribosomal subunit binding site has lower
affinity for aminoglycosides
Enzymatic modification
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Plasmid R factors that synthesize enzymes to
modify and inactivate antibiotic
Administration
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Inadequate absorption when oral
All parenteral, except neomycin
Neomycin
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Severe nephrotoxicity
Only topical use to reduce intestinal bacteria
Distribution
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Good body fluid penetration, except CSF
Accumulation in renal cortex and inner ear
lymph
All cross placenta
Metabolism
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Rapidly excreted into urine
Alter dose in renal insufficiency
General Therapeutic Uses
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Streptomycin
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Bacterial endocarditis (+ Pen)
Tuberculosis (combination)
Tularemia- hunters skinning infected animals
Gentamycin: combination with Pen/Ceph
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Urinary tract infections (E coli, enterobacter)
Pneumonia (pseudomonas, E coli, kleb)
Meningitis
Peritonitis
General Therapeutic Uses
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Tobramycin
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Same as gentamycin
Poor activity against enterococci
Amikacin
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Initial treatment of serious nosocomial gram
negative bacilli infections when resistance to
gentamycin and tobramycin
General Therapeutic Uses
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Netilmicin
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Kanamycin
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Serious infections with enterobacteriaceae and
other aerobic gram negative bacilli
Few indications
Neomycin
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Topical skin and mucosa infections
Adverse Effects
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Ototoxicity
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Nephrotoxicity
Neuromuscular paralysis
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High peak levels and long duration
Intraperitoneal/intrapleural high dose; myasthenia
gravis patients at risk
Contact dermatitis- neomycin topical
Monitor peak and trough plasma levels
Macrolides
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Many membered lactone ring where sugars or
amino acids are attached
Erythromycin
Azithromycin
Clarithromycin- more strep and staph
Dirithromycin
Troleandomycin
Telithromycin
Mechanism of Action
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Bind to 50 S subunit of bacterial ribosome,
inhibiting translocation step of protein
synthesis
Bacteriostatic activity
Better intracellular concentration with gram +
bacteria
Clarithro and Azithro more anaerobic
Inhibition of bacterial protein synthesis by
the macrolide antibiotics erythromycin, clarithromycin, and azithromycin
Resistance
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Inability of organism to take up antibiotic
Decreased affinity of binding site for antibiotic
Administration
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Adequate oral absorption
Intravenous: thrombophlebitis
Intramuscular: painful
Distribution
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Well into body fluids, except CSF
Diffuses into prostatic fluids
Accumulates in macrophages
Concentrated in liver
Penetrate well into abscesses
Metabolism
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Inhibits oxidation of other drugs through
interaction with cytochrome P-450 system
Excretion
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Concentrated and excreted in an active form in
the bile
Partial reabsorption through enterohepatic
circulation
General Therapeutic Uses
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Mycoplasma pneumonia
Syphilis- in penicillin allergic
Chlamydia- alternative to tetracycline; during
pregnancy
Legionellosis pneumonia
Corynebacterium diptheriae- carriers
Ureaplasma- urethritis
General Therapeutic Uses
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Alternative to penicillin in allergic patients
Clarithromycin (Biaxin) and Azythromycin
(Zithromax)
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COPD, pneumonia
Pharyngitis, tonsillitis
Acute maxillary sinusitis
Lower respiratory tract infections
Adverse Effects
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Epigastric distress
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Cholestatic jaundice
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Nausea, vomiting, pain, diarrhea
When estolate form is used
Ototoxicity
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High doses
Interactions
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Increases plasma concentration of digoxin
Inhibits hepatic metabolism of drugs
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Theophylin
Warfarin
Carbamazepine
Cyclosporin
Methylprednisolone
Terfenadine
Do not use in liver disease patients
Clindamycin
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Introduced in 1970
Semisynthetic derivative of lincomycin,
isolated from soil near Lincoln, Nebraska in
1965
Clindamycin produced by exchange of
hydroxyl group with chlorine atom at C7 of
lincomycin molecule
Clindamycin
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Binds to 50 S subunit of bacterial ribosomes to
inhibit protein synthesis
Bacteriostatic activity, but cidal action against
susceptible organisms in vivo
Spectrum
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Similar to erythromycin
Increased activity against gram + and anaerobes, staph aureus
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Bacteroides fragilis
Pharmacokinetics
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Well absorbed orally
Distributes well into body fluids, not CSF
Good bone penetration
Excreted into bile or urine
Therapeutic Uses
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Strep, Staph, pneumococci, anaerobic
infections
Purulent osteitis or other bone infection caused
by anaerobes
Adverse Effects
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GI distress
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Diarrhea
Pseudomembranous colitis- caused by clostridium
difficile
Superinfections
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Fungal overgrowth in oral cavity, intestine, vagina
Chloramphenicol
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Binds to 50 S ribosomal subinit
Bactericidal or static
Broad spectrum
Mechanism of inhibition of bacterial protein synthesis by chloramphenicol.
Pharmacokinetics
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IV or orally
Complete oral absorption
Excretion depends on conversion in liver to
glucuronide, then secretion in kidney
Therapeutic Uses
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Severe odontogenic infections threatening
orbital contents or brain
Penetrates well into brain and CSF
Typhoid fever- salmonella
Refractory meningitis by h. influenza, s.
pneumonia, n. meningitidis, rickettsia,
brucella, bacteroides
Adverse Effects
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Anemias
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Hemolytic, reversible/mild, aplastic
Gray baby syndrome
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Neonates if doses not adjusted
Low capacity to glucoronidate antibiotic and
underdeveloped renal function
Decreased excretion ability
Poor feeding then cyanosis then death
Streptogramins
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Quinupristin-dalfopristin
Rapidly bactericidal for most organisms except
Enterococcus faecium
Significantly inhibit CYP3A4
Oxazolidinones
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Linezolid
Active against gram-positive organisms
Bacteriostatic
Inhibits protein synthesis