Pharmacology Lec 5: Aminoglycosides and Tetracyclines PDF

8/7/2023 Anas Mohammed 1 Protein synthesis inhibitors By: Dr. Anas Mohammed Abdallah 8/7/2023 Anas Mohammed 2 Protein Synthesis Inhibitors A number of antibiotics exert their antimicrobial effects by targeting bacterial rib...

8/7/2023 Anas Mohammed 1 Protein synthesis inhibitors By: Dr. Anas Mohammed Abdallah 8/7/2023 Anas Mohammed 2 Protein Synthesis Inhibitors A number of antibiotics exert their antimicrobial effects by targeting bacterial ribosomes and inhibiting bacterial protein synthesis. Bacterial ribosomes differ structurally from mammalian cytoplasmic ribosomes and are composed of 30S and 50S subunits (mammalian ribosomes have 40S and 60S subunits). 8/7/2023 Anas Mohammed 3 8/7/2023 Anas Mohammed 4 Protein Synthesis Inhibitors Tetracyclines Aminoglycosides Macrolides Clindamycin Chloramphenicol 8/7/2023 Anas Mohammed 5 Tetracyclines Mechanism of action: Tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome. This action prevents binding of tRNA to the mRNA- ribosome complex, thereby inhibiting bacterial protein synthesis. Tetracycline, doxycycline and minocycline. 8/7/2023 Anas Mohammed 6 Tetracyclines Antibacterial spectrum: The tetracyclines are bacteriostatic antibiotics effective against a wide variety of organisms, including gram- positive and gram-negative bacteria, protozoa, spirochetes, mycobacteria, and atypical species. They are commonly used in the treatment of acne and Chlamydia infections (doxycycline). 8/7/2023 Anas Mohammed 7 Tetracyclines C. Resistance The most commonly encountered naturally occurring resistance to tetracyclines is an efflux pump that expels drug out of the cell, thus preventing intracellular accumulation. 8/7/2023 Anas Mohammed 8 TETRACYCLINES: Pharmacokinetics Absorption: Tetracyclines are adequately absorbed after oral ingestion. Both doxycycline and minocycline are available as oral and intravenous (IV) preparations. 8/7/2023 Anas Mohammed 9 TETRACYCLINES: Pharmacokinetics Distribution: The tetracyclines concentrate well in the bile, liver, kidney, gingival fluid, and skin. They bind to tissues undergoing calcification (for example, teeth and bones) or to tumors that have a high calcium content. 8/7/2023 Anas Mohammed 10 TETRACYCLINES: Pharmacokinetics Elimination: Tetracycline and doxycycline are not hepatically metabolized. Tetracycline is primarily eliminated unchanged in the urine, whereas minocycline undergoes hepatic metabolism and is eliminated to a lesser extent via the kidney. In renally compromised patients, doxycycline is preferred, as it is primarily eliminated via the bile into the feces. 8/7/2023 Anas Mohammed 11 Tetracyclines 8/7/2023 Anas Mohammed 12 Tetracyclines Adverse effects: 1. Gastric discomfort: Epigastric distress commonly results from irritation of the gastric mucosa and is often responsible for noncompliance with tetracyclines. 2. Effects on calcified tissues: Deposition in the bone and primary dentition occurs during the calcification process in growing children. This may cause discoloration and hypoplasia of teeth and a temporary stunting of growth. The use of tetracyclines is limited in pediatrics. 8/7/2023 Anas Mohammed 13 Tetracyclines Adverse effects: 3. Hepatotoxicity. 4. Phototoxicity. 5.Vestibular dysfunction: Dizziness, vertigo, and tinnitus may occur particularly with minocycline. 6.Contraindications: The tetracyclines should not be used in pregnant or breast-feeding women or in children less than 8 years of age. 8/7/2023 Anas Mohammed 14 Aminoglycosides Aminoglycosides are used for the treatment of serious infections due to aerobic gram-negative bacilli. Their clinical utility is limited by serious toxicities. E.g. Gentamicin, streptomycin, tobramycin and amikacin. 8/7/2023 Anas Mohammed 15 Aminoglycosides Mechanism of action: They bind the 30S ribosomal subunit, where they interfere with assembly of the functional ribosomal apparatus and/or cause the 30S subunit of the completed ribosome to misread the genetic code. 8/7/2023 Anas Mohammed 16 Aminoglycosides Antibacterial spectrum The aminoglycosides are effective for the majority of aerobic gram negative bacilli, including those that may be multidrug resistant, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter sp. Additionally, aminoglycosides are often combined with a β-lactam antibiotic to employ a synergistic effect, particularly in the treatment of Enterococcus faecalis and Enterococcus faecium infective endocarditis. 8/7/2023 Anas Mohammed 17 Aminoglycosides Resistance Resistance to aminoglycosides occurs via: 1) efflux pumps, 2) decreased uptake, and/or 3) modification and inactivation by plasmid-associated synthesis of enzymes. 8/7/2023 Anas Mohammed 18 AMINOGLYCOSIDES: Pharmacokinetis Absorption: The highly polar, polycationic structure of the aminoglycosides prevents adequate absorption after oral administration. All aminoglycosides (except neomycin… why??) must be given parenterally to achieve adequate serum levels. 8/7/2023 Anas Mohammed 19 AMINOGLYCOSIDES: Pharmacokinetis Distribution: All the aminoglycosides have similar pharmacokinetic properties. Due to their hydrophilicity, tissue concentrations may be subtherapeutic, and penetration into most body fluids is variable. Elimination: More than 90% of the parenteral aminoglycosides are excreted unchanged in the urine. Accumulation occurs in patients with renal dysfunction, and dose adjustments are required. 8/7/2023 Anas Mohammed 20 AMINOGLYCOSIDES Adverse effects: 1. Ototoxicity. 2. Nephrotoxicity. 3. Neuromuscular paralysis. 4. Allergic reactions. 8/7/2023 Anas Mohammed 21 THANKS