Protein Synthesis Inhibitors Flashcards by Deleted Deleted

4 aminoglycosides

streptomycin, gentamicin, tobramicin & amikacin

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3 tetracycines

doxycycline, tetracycline, minocycline

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1 lincosamide

Clindamycin

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1 oxazolidenone

Linezolid

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Protein synthesis inhibitors are static or cidal

Static except aminoglycosides (cidal)

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Protein synthesis inhibitors spectrum vs B-lactam

Broader than B-lactam

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Protein synthesis inhibitors general mechanism

ribosomes in eukaryotic cells sufficiently different from bacterial to provide selectivity

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Protein synthesis inhibotors tartgiting eleongation

Tetracyclines

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Target peptide bond formation

Clindamycin

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Target translocation or termination/recycline

Aminoglycosides

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Target translocation

Macrolides

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Action at 30S and 50S subunit of the Ribosome

Aminoglycosides

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Action at 30S subunit of the Ribosome

Tetracyclines

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Action at 50S subunit of the Ribosome

(i) Macrolides (ii) Clindamycin (iii) Linezolid

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Aminoglycosides - streptomycin

Mechanism
SE
Use
Resistance
Kinetics

Mechanism
Binds to two receptor sites: one on 16S RNA, and one on 23S RNA; ribosomal proteins involved also
- Wrong amino acids incorporated, i.e. misreading of mRNA (miscoding/30S site)
- Block initiation (streptomycin)
- Block translocation (30S site, other)
- Inhibits recycling (50S binding site)

SE
Deafness
Nephrotoxicity
Bone marrow suppression
Muscle weakness

Use
TB
Anerobic GNR: Gentamicin &amp; tobramycin
GP: SYnergistic with beta lactams
Anaerobes are resistant

Resistance

Inactivating enzymes
Membrane impermeability
Binding site mutation
Methylation of rRNA

Kinetics

Parenteral administration
renal excretion (alter)
post antibiotic effect
Extended interval dosing release (except in renal dysfunction)

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Why are aminoglycosides cidal)

Transport into bacterial cells:
Passive diffusion through the porin channels of the outer membrane

Energy-dependent, rate-limiting transport through the plasma membrane (inhibited under anaerobic conditions)

Mech-m of cytotoxicity:
Drug-induced mutated proteins inserted into the plasma membranes enhance uptake of the drug

3 drugs with concentration dependent killing

aminoglicosides
fluoroquinolones
metronidazole

Tetracyclines

Mechanism
Resistance

Mechanism
Binds to 30S subunit & blocks amino-acyl-tRNA binding resulting in the elongation block

Resistance

Rarely used in USA becuase of resistance
Efflux pumps
Reduced ribosomal 30 binding site
Enzyme inactivation

Spectrum for tetracylines

Bacteriostatic
Mycoplasma; Chlamydia; Legionella; Rickettsia (Rocky Mtn Fever); Borellia (Lyme disease); Strep pneumonia
Outpatient > hospital
Anti-parasites: malaria prevention

Only tetracyline that is hepaticaly cleared instead of renal

Doxycycline

Well absorbed from the gut - reduced absorption with food and chelators e.g. Al(OH)3

Good tissue penetration fairly large Vd

Tetracyline SE

Gastrointestinal intolerance (N/V/D)
Hepatotoxic
Skin photosensitivity
Never use in pregnancy, neonates, children- deposits in enamel of teeth and bone
Doxycycline is the onlytetracycline that can beused in renal failure

Drug to avoid giving pregnant women, neonates or childen

Tetracycines

Macrolids

Mechanism
Resistance mechanism

Mechanism
Binds to 50s to block polypeptide release

Resistance
Selectivity and Resistance - role of 23S rRNA- nucleotide 2058

Efflux or reduced permability

Production of esterase
S. pneumoniae or S. aureus

Azithromycin (macrolides)

Use & spectrum

Bacteriostatic

Bactericidal under certain conditions (organism, site, …)

GPC, Mycoplasma, Legionella, Chlamydia, H. influenzae, Mycobacteria

Can be used in penicillin-allergic individual

Respiratory tract infections

Macrolides phamcokinets

Well absorbed from GI tract Widely distributed, concentrated in cells Hepatic metabolism mainly

Macrolides with shortest & longest half lives

T1/2: clarithromycin - 3-7 h azithromycin - 68 h (once daily dosing)

Macrolides SE/Toxicity

Allergy-skin rashes hepatitis 2-5% Gastrointestinal upsets (N/V/D) Ototoxic-especially in elderly

Clindamycin Class Mechanism Resitance Clindamycin pharmacokinetics Specturm

Class A lincosamide Mechanism Binds to the 50S subunit on a 23S rRNA binding site and interferes with the peptide bond formation Binding site partially overlaps with macrolides Resistance Mutual interference if co-prescribed with the macrolides Resistance mechanisms same as with macrolides Pharmacockinets Well absorbed from the gastrointestinal tract Good tissue penetration (large Vd) concentrated intracellularly T1/2 2-2.5h Hepatic metabolism Spectrum Bacteriostatic Narrow spectrum GPC (Staph. and Strep.); oral and bowel anaerobes (50% Bacillus fragilis) Often used for deep seated infections (e.g intrabdominal infections) in combination with other agents Used for skin and soft tissue infection + dental

SE of clindamycin

Bacteriostatic Narrow spectrum GPC (Staph. and Strep.); oral and bowel anaerobes (50% Bacillus fragilis) Often used for deep seated infections (e.g intrabdominal infections) in combination with other agents Used for skin and soft tissue infection + dental

Linezolid ``` Class Mechanism Resistance Spectrum Kinetics SE ```

Class Oxazolidinones Mechanism Binds to 23S rRNA of 50S at the A site Blocks formation of the initiation complex Resistance Mutation of 23S rRNA binding site No cross-resistance with other drug classes ``` Pharmacodynamics and spectrum Wide range of GP organisms susceptible Bacteriostatic against staph and enterococci Bacteriocidal for most strep Used to treat VRE, VRSA and MRSA ? Potential new agent for Myco. TB ``` Pharmacokinetics I/V & oral - 100% oral bioavailability Renal (30%) and hepatic clearance (65%) ``` Side Effects/Toxicity Hematologic : leukopenia/thrombocytopenia & aplastic anemia Gastrointestinal intolerance: N/V/D Biochemical hepatitis Drug interactions: weak MAO-I ```