26) Protein Synthesis Inhibitors Flashcards
Bacterial protein synthesis inhibitors (30s)
- Aminoglycosides
- Glycylcycline (Tigecyclin)
- Tetracycline (t-RNA binding)
Bacterial protein synthesis inhibitors (50s)
- Oxazolines (initiation inhibitors)
- Peptidyl transferase (Chloramphenicol)
- Transcription/translocation inhibitors
50s transcription/translocation inhibitors classificaitons
- Macrolides
- Ketolides
- Lincosamides
- Streptogramins
Initiation
- mRNA joins with 30S and with t-fMet-tRNA (t-RNA linked to formylated methionine)
- 50S joins the 30S/ t-fMet-tRNA to form the 70S complex
- t-fMet-tRNA occupies the P-site
Elongation
- 30S decodes the codon
- 50S catalyzed the formation of the peptide bond (bond between amino acids)
Termination
- It releases factors that recognize the terminal codon
- Discharge the newly synthesized protein
- Dissociates the ribosome-mRNA complex
Aminoglycosides MOA
- Binds to the cytosolic membrane-associated bacterial ribosome
- Disturbs peptide elongation by changing the shape of 30S ribosomal subunit –> inaccurate mRNA translation
Tetracycline/Glycylcycline MOA
- Binds to the 30S ribosomal subunit
- Inhibits the binding of aminoacyl-tRNA to the mRNA (A-site= acceptor) translation complex
- Inhibits initiation of translation
Oxazolidinones MOA
- Binds to ribosomal subunit 50S
- Inhibits the initiation process in protein synthesis by preventing the formation of 50/30S complex
Chloramphenicol MOA
- Prevents protein chain elongation by inhibiting the peptidyl transferase activity of the bacterial ribosome of 50S
- Leads to the inhibition of peptide bond formation
Macrolides, ketolides, Streptogramins and lincosamide MOA
- Binds to the P binding site of the 50S ribosomal subunit
- Prevents peptidyl transferase
- Inhibits translocation step (where the polypeptide is transferred from P to E site) and affects elongation
Aminoglycosides coverage/administration
- Gram-negative
- Not orally bioavailable, given intravenously (IV)
Aminoglycosides and beta-lactam combination
- Beta-lactam increase cell wall permeability and facilitate the uptake of aminoglycosides
- Boosts its effect
Aminoglycosides side effects
- Ototoxicity (they accumulate in inner ear)
- Nephrotoxicity (they accumulate in proximal tubule)
- Neuromuscular blockade (respiratory paralysis)
Aminoglycosides (names)
- Gentamycin
- Tobramycin
- Amikacin
- Streptomycin
Gentamycin warning
- Cross-sensitivity to other aminoglycosides
- Superinfection with CDAD (C. difficile associated diarrhea)
Tobramycin box warning
- Not used during pregnancy (fatal)
ALL aminoglycosides US box warning
- Neurotoxicity (as ototoxicity) and nephrotoxicity; use of potent diuretics
ALL aminoglycosides ADRs
- Electrolyte alteration
- Hearing impairment
- Neuromuscular disorder
- Renal problem
- Visual disorder
- Respiratory depression
- Fever
ALL aminoglycosides cardio ADRs
- Edema
- Hypo/hypertension
- Phlebitis
- Brain disease, confusion, seizure;
- Alopecia
- Urticaria;
ALL aminoglycosides endocrine ADRs
- Hypocalcemia
- Hypokalemia
- Hypomagnesemia
- Hyponatremia
- Weight loss
ALL aminoglycosides hematologic ADRs
- Agranulocytosis
- Anemia
- Eosinophilia
- Granulocytopenia
- Leukopenia
- Purpura
- Thrombocytopenia
Additional ADR for Tobramycin
- Increase LFTs
ALL aminoglycosides metabolism
- Not known
- Renally eliminated
- Poor distribution in CSF and ocular because it is hydrophilic
- Less than 20% protein binding
Tetracyclines ADRs
- Kidney toxicity and GI distress (contraindicated in renal impairment)
- GI distress (esophageal ulceration especially doxycycline)
- Cutaneous photosensitivity (especially tetracycline)
- Bone development abnormalities in pediatrics (teeth becoming discolored because of UV-absorbed properties of tetracyclines; NOT GIVEN IN CHILDREN)
Oral co-administration of tetracyclines with di/tri-valent cations (like calcium, magnesium, aluminum; antacids…) can lead to
- Chelation of tetracycline
- Thus, it decreases absorption
Tetracyclines (names)
- Tetracycline
- Doxycycline
- Minocycline
