Protein Synthesis Inhibitors Flashcards
1
Q
Classes of protein synthesis inhibitors & examples
A
30S subunit inhibitors
- Aminoglycosides (streptomycin, gentamicin, amikacin, tobramycin, neomycin)
- Tetracyclines (tetracycline, doxycycline, minocycline, tigecycline)
50S subunit inhibitors
- Macrolides (erythromycin, clarithromycin, azithromycin)
- Clindamycin
- Linezolid
2
Q
Mechanism of action of aminoglycosides
A
- Blocks initiation of protein synthesis
- Binds to 30s subunit of bacterial ribosome - interfere with proof-reading process causing increased rate of error of translation
- Misreading of genetic code - translational inaccuracy - prevents formation of initiation complex at P site
- most effective in alkaline, anaerobic environments
3
Q
PK of aminoglycosides
A
ROA
- streptomycin, gentamicin, amikacin, tobramycin - IM/IV, given over 30-90 min
- gentamicin - oral (paed syrup), eye & ear drops
- amikacin - oral (paed syrup)
- tobramycin - eye drops, ointment
- neomycin - oral (given before intestinal surgery to sterilize gut)
- poor penetration into CSF
- excreted renally unchanged
4
Q
Spectrum of activity & uses of aminoglycosides (4)
A
Gram neg anaerobes & aerobes
- With broad spectrum beta lactams - for (A) progressive severe sepsis & septic shock (B) sepsis w/o shock if pathogen is suspected to be MDR gram neg
- Pyelonephritis (A) with beta lactams/quinolones as empirical treatment (B) alone if allergic to those
- Serious infections by MDR gram neg
- Endocarditis when beta lactams are insufficient
5
Q
Toxicity of aminoglycosides & contraindications (4+3)
A
- Nephrotoxicity - inhibits protein synthesis in renal cells - necrosis of PT cells - ATN - ARF
- Ototoxicity - amikacin results in more hearing damage, streptomycin/gentamicin vestibular
- Neuromuscular block
- Hypersensitivity - rash
- Renal impairment eg elderly - impaired renal fn
- Neuromuscular blocking agents & myasthenia gravis
- Amphotericin B, cephalosporins, NSAIDs, vancomycin
6
Q
Mechanism of action of tetracyclines
A
- Inhibits elongation of protein synthesis
- Binds reversibly to A site on 30s subunit - prevents addition of new amino acids to nascent peptide chain
- Blocks attachment of charged aminoacyl-tRNA to A site
7
Q
Mechanism of resistance of aminoglycosides (3)
A
- Produce enzymes that inactivate aminoglycosides esp enterococci
- Decrease cell wall permeability to aminoglycosides (overcome with cell wall synthesis inhibitors)
- Decrease affinity of binding site on 30s subunits via mutation
8
Q
Mechanism of resistance of tetracyclines (4)
A
- Enzymes that inactivate tetracyclines
- Decrease cell wall permeability to tetracyclines
- Ribosomal protection via production of proteins that interfere with tetracycline binding
- Efflux pumps
9
Q
PK of tetracyclines
A
ROA
- Tetracycline - oral, topical
- Doxycycline, Minocycline - oral
- Tigecycline - IM/IV
- Absorbed best before food (impaired by food, alkaline pH, cations)
- Doxycycline - most lipid soluble, conjugated in the liver, excreted in bile
- Tigecycline is minimally metabolized, excreted in bile & urine
10
Q
Spectrum of activity & uses of tetracyclines (2)
A
- Broad spectrum - gram pos & neg, aerobic/anaerobic, mycoplasma, rickettsia, chlamydia, amoeba
Tigecycline - extended spectrum - MRSA, VRE, actinobacter, pen-resistant strep pneumoniae, kleb pneum, e coli, enterobacter - Strains of PAE, proteus, klebsiella, pathogenic E coli - resistant
- General organ infections - bronchopneumonia, bacterial enteritis, cholangitis, prostatitis, pyodermatitis, UTI
- Specific - actinomycosis, anthrax, chancroid, chlamydiosis, plague, syphilis
11
Q
Toxicity of tetracyclines & contraindications (6+5)
A
- GIT related esp oral tetracycline due to gut irritation - minimise by taking with food
- Teeth discolouration & enamel dysplasia - chelation of Ca by tetracycline deposits in teeth buds
- Bone growth inhibition & deformity - chelation of Ca in growing ends of bones
- Superinfections (CDAD, enterocolitis, thrush)
- Thrombophlebitis - Tigecycline
- Renal function deterioration
- Hepatic enzyme inducers (phenytoin, carbamazepine, phenobarbitone) can shorten plasma half life of doxycycline by 50%
- Severe liver impairment
- 2nd trimester pregnancy
- Nursing mothers
- Children up to 8 years
12
Q
Mechanism of action of macrolides
A
- Bind reversibly to P site on 50s subunit of ribosome
2. Inhibits peptidyl transferase from adding the growing peptide to the next amino acid & inhibits translocation
13
Q
Mechanism of resistance of macrolides (3)
A
- Efflux pumps
- Produces esterases - hydrolyse macrolides
- Modify 50s binding site by methylase
14
Q
PK of macrolides
A
ROA
- Erythromycin - oral, IV
- Clarithromycin - oral
- Azithromycin - oral, syrup, IV
- penetrates tissues readily including placenta, except CSF
- accumulates in leukocytes & macrophages - concentrates at site of infection
- erythromycin - partially inactivated in the liver, mainly excreted unchanged in bile
- clarithromycin - hepatically metabolised, renally excreted
15
Q
Spectrum of activity & uses of macrolides (3)
A
Erythromycin - slightly wider than penicillin - legionella, mycoplasma, chlamydia, ricketssia, enteric infection by campylobacter, vibrio cholerae
Clarithromycin - as above + H.influenze, H. pylori
Azithromycin - as above + salmonella, shigella, chlamydia trachomatis, neisseria gonorrhea
- Community acquired pneumonia by gram pos/neg aerobes, H. influenzae
- Clarithro/Azithro - triple therapy for H. pylori
- Azithro + ceftriaxone - resistant N. gonorrhea
