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
Tetracycline CI/warnings
- Increase BUN
- Intracranial hypertension
- Photosensitivity
- Superinfection and CDAD
Tetracycline ADRs
- Thrombophlebitis
- Skin photosensitivity
- Dental discoloration
- Esophagitis
- Azotemia
- Hepatotoxicity
- Renal failure
- Tissue hyperpigmentation
Tetracycline metabolism
- Major substrate of CYP3A4
- Renal and fecal excretion
- Wide distribution but poor to CSF
- 60% protein binding
- Half life: 6-8 hours
Doxycycline ADRs
- Hypertension
- Increased lactate dehydrogenase
- Increased serum glucose
- Diarrhea
- Increased serum aspartate aminotransferase
- Nasopharyngitis
Doxycycline metabolism
- Not known
- 90% protein binding
- Renal and fecal excretion
- Half life: 16 hours
Minocycline CI/warnings
- Autoimmune syndrome (lupus-like)
- Dizziness, mental alertness
- Hepatotoxicity
Minocyclin ADRs
- Ddizziness
- Urticaria
- Tinnitus
Minocycline metabolism
- Renal and fecal excretion
- 60% protein binding
- Half life: 16 hours
ALL tetracyclines CI/warning
- Hypersensitivity
- Use in infants and children <8 years old or during 2nd/3rd trimester of pregnancy
- Breast feeding
Macrolides (names)
- Azithromycin
- Clarithromycin
- Erythromycin
- Telithromycin
ALL macrolides CI/warning
- Hypersensitivity
- QT prolongation
- Superinfection and CDAD
- Cardiac risk
- Exacerbates myasthenia gravis
Myesthinea Gravis
- Neuromuscular disorder that causes weakness in the skeletal muscles
- Facial paralysis
- Difficulty breathing, swallowing and talking
- Drooping eyelids
- Double vision
ALL macrolides ADRs
- Nausea, vomiting, diarrhea
- Photosensitivity
- Candidiasis
Azithromycin ADRs
- Palpitations
- Vaginitis
- Decreased neutrophils
- Increased LFTs
- Increases BUN, serum creatinine
Azithromycin metabolism
- Extensive distribution (not in CSF)
- 50% protein binding
- Hepatically metabolized
- Renal and biliary excretion
Clarithromycin CI/warning
- Hepatic effects
Clarithromycin ADRs
- Insomnia
- Skin rash
- Increased BUN
Clarithromycin metabolism
- 50% protein binding
- Hepatically metabolized
- Renally and excreted in the feces
Erythromycin ADRs
- Hearing loss
- Hepatitis
- Interstitial nephritis
Erythromycin metabolism
- 80% protein binding
- Hepatically metabolized
- Renally excreted and in the feces
Telithromycin CI/warning
- US box warning: Contraindicated in myasthenia gravis
- Hepatic effects
- Syncope
- Visual disturbances
Telithromycin ADRs
- Headache
- Dizziness
- Blurred vision
- Thrombocytopenia
Telithromycin metabolism
- 60% protein binding
- Hepatically metabolized
- Renally excreted and in the feces
Macrolides that are both substrates AND inhibitors of CYP3A4
- Clarithromycin
- Erythromycin
- Telithromycin
Tigecycline (glycylcycline family) CI/warning
- US Box warning of increased mortality
- Hypersensitivity
- Cross reactivity with tetracyclines
- Anti-anabolic effect with tetracycline (increased BUN, azotemia, acidosis, and hyperphosphatemia)
- Hepatotoxicity
- Photosensitivity
- Pancreatitis
- Pseudotumor cerebri
- Superinfection
Tigecycline (glycylcycline family) ADRs
- NVD, headaches
- Phlebitis, skin rash
- Hyponatremia, hypocalcemia, hypoglycemia
- Anorexia, hypoprotenemia
- Vaginitis
- Candidiasis
- Increased INR, LFT, BUN
- Eosinophilia
- Hyperbilirubinemia
Tigecycline (glycylcycline family) metabolism
- Not known
- 70% protein binding
- Hepatically metabolized and renal/fecal excretion
Chloramphenicol CI/warning
- US Box warning: blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia)
- Hypersensitivity
- Gray syndrome (cyanosis) associated with serum levels more than 50mcg/ml
- Superinfection with CDAD
Chloramphenicol ADRs
- Confusion, delirium
- Urticaria, aplastic anemia
- Diarrhea
- Bone marrow depression
- Optic neuritis
Chloramphenicol metabolism
- Hepatically metabolized
- 40% protein binding
- Good distribution including CSF
- Renally excreted
Clindamycin (lincosamide family) CI/warning
- US Box warning for fatal colitis with CDAD
- Hypersensitivity (anaphylactic shock)
- Superinfection
Clindamycin (lincosamide family) ADRs
- Hypotension, thrombophlebitis
- Metallic taste
- Rash azotemia
- Proteinuria, agranulocytosis
- Neutropenia, thrombocytopenia
- DRESS syndrome
Clindamycin (lincosamide family) metabolsim
- Metabolized by CYP3A4
- 90% protein binding
Linezolid (Oxazolidinone family) CI/warning
- Hypersensitivity
- Lactic acidosis
- Myelosuppression
- Optic neuropathy
- Serotonin syndrome (serotonin degradation is MAO mediated; hyperthermia; muscle rigidity; rapid fluctuation in mental signs)
- Superinfection
Linezolid (Oxazolidinone family) ADRs
- NVD
- Decreased WBC and platelets
- Skin rash
- Increased amylase
- Vulvovaginal candidiasis
- Increased LFTs, BUN, and creatinine
Linezolid (Oxazolidinone family) metabolism
- Inhibits monoamine oxidase
- 30% protein binding
- Hepatically metabolized
Tedizolid (Oxazolidinone family) CI/warning
- Superinfection
- Neutropenia
Tedizolid (Oxazolidinone family) ADRs
- Flushing, urticaria
- Hypertension, tachycardia
- NVD
- Oral candidiasis
- Visual impairment
- Increase LFT
- Decrease WBC, platelets, hemoglobin
Tedizolid (Oxazolidinone family) metabolism
- Inhibit BCRP/ABCG2
- 80% protein binding
- Fecal excretion
Quinupristin/dalfopristin
(Streptogramin family) CI/warning
- Hypersensitivity
- Arthralgias
- Hyperbilirubinemia
- Phlebitis
- Superinfection
Quinupristin/dalfopristin
(Streptogramin family) ADRs
- Thrombophlebitis
- Headache
- Skin rash
- Increased lactate dehydrogenase
- NVD
- Anemia
Quinupristin/dalfopristin
(Streptogramin family) metabolsim
- Inhibit CYP3A4
- Metabolism: conjugated with glutathione
- Fecal excretion
