Protein Synthesis Inhibitors Flashcards
What do the protein synthesis inhibitors act on?
30S, 50S Ribosomal subunits
What class of drugs are used against 30S?
Tetracyclines, glycylcycline, aminoglcosides
How does tetracycline work?
Tetracyclines concentrate intracellularly and bind irreversibly to 30S subunit of bacteria ribosome, prevent binding of tRNA to the A site of the mRNA-ribosome complex, thus inhibiting protein synthesis
What to avoid when taking tetracyclines?
Food(best on empty stomach)
Dairy products containing calcium –> decrease absorption and F
Can pregnant women take tetracyclines?
No.
What does tetracyclines bind to during distribution?
Tissues undergoing calcification
(Bones/teeth)
How is CSF penetration for tetracyclines?
Moderate
(More for mino and doxycycline)
Can tetracyclines be taken with beta-lactams?
No. Avoid administering both
Is tetracyclines effectuve against Pseudomonas?
No
Which tetracyclines be used against MRSA?
Doxycycline
How are tetracyclines administered?
Orally
What does tetracycline cover?
Gram negative and positive(MRSA)
- Rickettsia
- Chlamydia
- Mycoplasma
- Vibrio cholerae
- Yersinia Pestis
- S pneumoniae
- Bacillus anthracis
What can treat acne too?
Doxycycline,minocycline
How are the tetracyclines excreted?
Tetracycline: R
Doxycycline: unchanged in bile n urine
Minocycline: Liver
Name a glycylcycline
Tigecycline
Why are glycylcycline developed?
Overcome resistance from efflux pumps and/or ribosomal protection with a stringer affinity to active site of 30S, blocking entry of transfer RNA
How is tigecycline administered?
IV, poor oral F
Is it good for bloodstream infections?
No
How is tigecycline excreted
Bile/fecal
When is dose adjustment for tigecycline needed?
Hepatic impairment, no need for renal impairment
What is tigecycline used for?
- MRSA
- multi-drug resistant streptococci
- Vancomycin-resistant enterococci (VRE)
- Extended spectrum beta-lactamase(ESBL) gram negative bacteria, resistant to carbepenem
Can tigecycline be used against Pseudomonas?
No.
ADR of tigecycline
- GI discomfort (take on empty stomach)
- Discolouration of teeth stunt growth
- Hepatotoxicity
- Phototoxicity (use sunscreen)
- Vestibular dysfunction: dizzyness, vertigo, tinnitus more for minocycline.
- Renal SE
- Superinfection for prolonged use (CDAD >2m)
CI of tetracyclines/tigecycline
Pregnant women, children <8yo
Oral Sulfonylurea
How does aminoglycosides work?
Aminoglycoside diffuse through aqueous porin channels for gram-negative bacteria and transport across inner membrane via active transport(can be inhibited by anaerobic conditions, drop in pH and hyperosmolarit)
Aminoglycosides distorts ribosome structure by binding to them and 1. blocking formation of initiation complex
2. Causing misreading of codons as wrong amino acyl tRNA are able to bind to A site without matching codon present in mRNA in that position
3. Inhibit translocation
Aminoglycosides has a synergistic effect with _____________ against ___________ though they work primarily against ______
Cell wall synthesis inhibitors
Gram positive bacteria
Aerobic gram negative bacteria and mycobacteria
Aminoglycosides has a _______-dependent killing
Concentration
Administration of aminoglycosides
Mainly Parenteral (except neomycin), poor oral F due to polar
Can Aminoglycosides be used for CSF infections?
No
Excretion of aminoglycosides
Renal
Name 5 aminoglycosides
- Gentamicin
- Tobramycin
- Amikacin
- Streptomycin
- Neomycin
What does aminoglycosides cover?
Gram negatives
- Klebsiella
- Escherichia coli
- Pseudomonas
- Acinetobacter
- 2nd line for tuberculosis
What has the widest range among aminoglycosides?
Amikacin IM/IV/IT
______ is used with _____ to treat enterobacteriaceae (Klebsiella, Proteus) + enterococcal endocarditis
Gentamicin/streptomycin
Penicillin/ceftriaxone
What aminoglycoside can be used against Pseudomonas?
Tobramycin, Amikacin
Which aminoglycosides is most toxic?
Neomycin (oral and topical)
What is applied topically for bowel prep for surgery?
Neomycin
CI for neomycin
Intestinal obstruction, gastric/ intestinal ulcer, hx of Aminoglycoside hypersensitivity
Excretion for aminoglycosides
Renal except neomycin(faeces)
What is amikacin ineffective against?
Anaerobic gram positive strains
What is streptomycin ineffective against?
Aerobic GNR
ADR of Aminoglycosides
- Ototoxicity
- Nephrotoxicity
- Neuromuscular paralysis
- Hypersensitivity rxns: rash, contact Dermatitis
- CI: Pregnancy, <8yo
Monitoring for aminoglycosides
Renal, hearing, myasthenia gravis
- avoid use with other nephrotoxic drugs (Amphotericin B, Vancomycin, NSAIDs and neuromuscular blocking agents)
- TDM, RFT (Urea, creatinine, electrolytes)
6 amiNOglycosides
NO protein synthesis
mainly aerobic gram Negative Organisms
NO use in pregnancy
NO oral administration
NO CSF pentration
Nephro and Ototoxicity
Factors tt predispose to Nephro/ototoxicity
- Dose
- Duration >5d
- Concomitant nephrotoxic drugs
- Age (renal function)
- Genetic
Mechanisms of resistance against aminoglycosides
- Increased efflux pumps
- Aminoglycoside inactivating enzyme production
- Altered 30S
- Inhibition of Aminoglycoside uptake
What classes of drugs are used for protein synthesis inhibition of 50S?
Macrolides
Lincosamide - Clindamycin
Oxazolidinones - Linezolid
Macrolides MOA
inhibit 50S ribosomal subunit, inhibiting translocation step such that peptide chain is unable to move to P site
Name 3 macrolides
- Erythromycin
- Clarithromycin
- Azithromycin
Cns penetration of macrolides?
Poor
Macrolides are effective against?
Atypicals,
Substitute for penicillin allergy
Mocrolide clearance
Ec - hepatic
A - biliary,excretion, unchanged in faeces
ADR of macrolides
- GI
- Hepatotoxicity
- Ototoxicity
- QTc prolongation
- ddi - cyp450 inhibitor
Clindamycin MOA
Binds to 50s subunit, inhibit p synthesis,
Antagonistic effect with macrolides (cross resistance)
Clindamycin is effective against?
MRSA
Streptococcus
PR anaerobic bacteria (bacteroides, clostridioides perfringen)
Entry into CNS for clindamycin
Poor
ADR clindamycin
- Esophageal irritation - take with a glass of water
- GI DV
- CDAD
Resistance to clindamycin
Altered 50s by aa substitution
Alterations in 23s by methylation and nucleotidylation of hydroxyl grp of clindamycin
Linezolid covers?
Gram positive bacteria
Moa of linezolid
Binds to 23s ribosomal rna of 50s and prevents 70s initiation complex
Cautions in linezolid
DNU within 2w of MAOI
Avoid tyrosine containing food and serotonergic drugs –> hypertensive crisis
