Antibacterial Protein Synthesis Inhibitors PDF 2024-2025

Level II: Semester I Antibacterial Protein synthesis inhibitors  Sameh Ahmad Abdelghany 2 MD,PhD ❑ CONTACT Email: [email protected] Tel: 0790601974  ILOs 1. Classify Inhibitors Of protein Synthesis 2. Explain T...

Level II: Semester I Antibacterial Protein synthesis inhibitors  Sameh Ahmad Abdelghany 2 MD,PhD ❑ CONTACT Email: [email protected] Tel: 0790601974  ILOs 1. Classify Inhibitors Of protein Synthesis 2. Explain The Mechanism Of Action, Of Inhibitors Of protein Synthesis 3. Recognize Therapeutic ,Uses & Adverse effect Of Inhibitors Of protein Synthesis Lecture Outline Classification of protein synthesis Inhibitors Inhibitors of 50s ribosomal subunit Protein Inhibitors of 30s synthesis ribosomal subunit Inhibitors  5 ❑ Classification of protein synthesis Inhibitors I. Inhibitors of 30s ribosomal subunit: 1) Aminoglycosides 2) Tetracyclines II. Inhibitors of 50s ribosomal subunit: 1) Macrolides 2) Lincosamides 3) Chlramphenicol 4) Linezolid 5) Quinupristin–Dalfopristin  6 Protein synthesis Inhibitors  7 I- Inhibitors of 30s ribosomal subunit 1) Aminoglycosides Pharmacokinetics: ▪ Are polar compounds, not absorbed orally or widely distributed into tissues ▪ Renal elimination proportional to GFR, and major dose reduction needed in renal dysfunction  8 I- Inhibitors of 30s ribosomal subunit 1) Aminoglycosides Mechanism of action: ▪ bind 30s subunit so inhibit protein synthesis ▪ This leads to misreading of the genetic code( bactericidal) ▪ Effective against Gram –ve bacteria e.g Pseudomonas infections ▪ Resistance: inactivation by plasmid- associated synthesis of enzymes.  9 Aminoglycosides mechanism of action  10 Examples: ▪ Gentamicin , amikacin , tobramycin,streptomycin, neomycin. General considerations: ▪ Useful spectrum includes gram-negative rods; gentamicin, tobramycin, and amikacin often used in combinations ▪ Synergistic actions occur for infections caused by enterococci (with penicillin G or ampicillin) and P. aeruginosa (with an extended spectrum penicillin or third-generation cephalosporin) ▪ Streptomycin used in tuberculosis  11 Adverse effects: 1) Nephrotoxicity: In form of reversible renal tubular damage. 2) Ototoxicity: includes deafness (irreversible) and vestibular dysfunction (reversible) 3) Neuromuscular blockade: may enhance effects of skeletal muscle relaxants  12 2) Tetracyclines Pharmacokinetics: ▪ Kidney for most (↓ dose in renal dysfunction) ▪ Liver for doxycycline ▪ Chelators: tetracyclines bind divalent cations (Ca2+, Mg2+, Fe2+), which ↓ their absorption Mechanism of action: ▪ bind 30s subunit so inhibit protein synthesis ▪ prevent the binding of aminoacyl tRNA ta the acceptor site on the mRNA-ribosome complex and addition of amino acids to the growing peptide, thus inhibiting bacterial protein synthesis.  13 Mechanism of action  14 ▪ Effective against Most gram-positive & Most gram-negative bacteria with good activity versus chlamydial and mycoplasmal species, H. pylori (GI ulcers), Rickettsia, Borrelia , Brucella, Vibrio, and Treponema Examples: ▪ Older preparations (chlortetracycline, oxytetracycline) ▪ Semisynthetic derivatives: Doxycycline, Minocycline N.B: Glycylcycline: e.g Tigecycline: derivative of minocycline with broader spectrum. It has activity against a variety of gram-positive and gram-negative bacteria, including MRSA  15 Adverse effects: 1) GIT upset: Nausea, vomiting, and diarrhea 2) Super infection: ▪ Pseudomembranous enterocolitis should be treated with metronidazole. 3) Yellow discoloration of teeth and deformity of bone 4) Phototoxicity (doxycycline) 5) Liver dysfunction during pregnancy at very high doses  Review Q.1 16 ❑ A 77-year-old woman was started on antibiotics for pneumonia treatment. After 3 days of antibiotic therapy, the serum creatinine doubled. Which of the following antibiotics is most likely responsible for this increase in serum creatinine? a. Doxycycline b. Clarithromycin c. Gentamycin d. Linezolid e. Clindamycin  17 II- Inhibitors of 50s ribosomal subunit 1) Macrolides Pharmacokinetics: ▪ Absorption of erythromycin is affected by food and HCl. To minimize destruction and enhance absorption, erythromycin is administered as esters salts. ▪ Newer macrolides are acid stable and can be given orally. ▪ reach all body fluids including prostate, placenta and milk but only small amounts can penetrate to CSF.  18 ▪ Azithromycin concentrated in neutrophils, macrophages and lung tissue, so have long t1/2 (given once daily) and useful against intracellular organisms. ▪ Macrolides are concentrated in liver and excreted primarily in active form via bile with only low levels found in urine. Examples: Erythromycin – Azithromycin – Clarithromycin Uses: if allergy to penicillin  19 Mechanism of action: ▪ bind reversibly to the 50S ribosomal subunit and inhibit bacterial protein synthesis ▪ Effective against a number of organisms, including gram- positive bacteria and some gram-negative bacteria, e.g. Neisseria, H. influenza, and intracellular microorganisms (Mycoplasma species, legionella and Chlamydia). ▪ Bacterial resistance primarily due to increased active efflux  20 Mechanism of action  21 Mechanism of action  22 ❑ Adverse Reactions i. Gastrointestinal Effects: o Anorexia, nausea, vomiting, and diarrhea. ii. Reversible Liver Toxicity(Erythromycin) iii. Increased QT interval iv. Drug Interactions: o Erythromycin metabolites inhibit cytochrome P450 enzymes , causing increase in the serum concentrations of theophylline, oral anticoagulants(warfarin).  2) Lincosamides (Clindamycin) 23 ▪ Not a macrolide, but has the same mechanisms of action and resistance ▪ Narrow spectrum: gram-positive cocci (including community-acquired (MRSA) and anaerobes, including B. fragilis (backup drug) ▪ Concentration in bone has clinical value in osteomyelitis due to gram-positive cocci Side effect: pseudomembranous colitis (most likely cause)  3) Chloramphenicol 24 Mechanism of action: ▪ binds reversibly to the bacterial 50S ribosomal subunit and inhibits protein synthesis at the peptidyl transferase reaction(bacteriostatic). ▪ Broad spectrum antibiotic, active against both Gram-negative & Gram-positive. ▪ limited use because of its severe toxicity. ▪ Used as an alternative to penicillin and cephalosporins for typhoid fever, and anaerobic infections ▪ Used also as eye drops for eye infections. 3) Chloramphenicol 25  26 Side effects: 1) Gray baby syndrome ▪ neonates because their liver not well developed. Chloramphenicol remain unmetabolized. ▪ cyanosis, collapse, abdominal distension, and shock. 2) Aplastic anemia and bone marrow suppression. 3) Inhibition of cytochrome P-450 enzymes  4) Linezolid 27 Mechanism of action: ▪ It binds to 50 s subunit bacterial ribosome to inhibit protein synthesis (bactericidal). ▪ It is active against gram positive cocci especially vancomycin and methicillin- resistant staph. aureus. Side effects: 1) Gastrointestinal disturbance 2) Thrombocytopenia(serious) 4) Linezolid 28  5) Quinupristin–Dalfopristin 29 Mechanism of action: ▪ It binds to 50 s subunit bacterial ribosome to inhibit protein synthesis (bactericidal). ▪ It is active against gram positive cocci especially vancomycin and methicillin-resistant staph. aureus. Side effects: ▪ Inflammation and pain at the infusion site ▪ Arthralgia , myalgia ▪ GIT upset.  Review Q. 30 ❑ A man with a skin infection due to methicillin-resistant Staphylococcus aureus is treated with linezolid. Which adverse effect is associated with this antibiotic? a. myalgia and arthralgia b. nystagmus and vertigo c. thrombocytopenia d. discoloration of body fluids e. flushing and hypotension  References 31 ▪ Goodman and Gilman’s: The Pharmacological basis of therapeutics, latest edition. McGraw-Hill. ▪ Pharmacology, H.P. Rang M. M. Dale and J.M. Ritter, latest edition, Churchill Livingstone. ▪ Elsevier's Integrated Pharmacology, M. Kester, K.E. Vrana, S.A. Quraishi and K.D. Karpa, latest edition ▪ Basic and Clinical Pharmacology, Bertram G Katzung and Anthony J Trevor, latest edition, McGraw-Hill ▪ Lippincott’s illustrated review: Pharmacology, Whalen, K., Wolters kluwer india Pvt Ltd.  thanks For Watchi ng