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Amphenicols: Broad-Spectrum Bacteriostatic Drugs

Learn about chloramphenicol, thiamphenicol, and florfenicol, their usage, pharmacokinetics, antimicrobial spectrum, clinical uses, adverse effects, and contraindications. Understand their mode of action, bacterial resistance, and drug interactions.

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Amphenicols: Broad-Spectrum Bacteriostatic Drugs

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  1. AMPHENICOLS A group of broad spectrum,bacteriostatic drugs Chloramphenicol (the parent compound) Initially obtained from streptomyces venezuelae in 1947 but now it is manufactured synthetically

  2. Chloramphenicol

  3. Thiamphenicol

  4. Florfenicol

  5. Chloramphenicol Para-nitrophenyl group Not important for antibacterial activity Implicated in irreversible mylosuppression May be changed to ortho or meta positions or even it can be replaced by halogens

  6. Thiamphenicol Semi-synthetic derivative of Chloramphenicol Substitution of p-nitrophenyl group with sulphomethyl group (CH3SO2) Less lipophillic and potent

  7. Florfenicol Fluorinated analogue of Thiamphenicol Substitution of hydroxyl group with fluorine Less susceptible to microbial inactivation No risk of irreversible aplastic anemia

  8. Mode of action Inhibit protein synthesis in susceptible micro-organisms & to a lesser extent in mammalian cells Penetrate into bacterial cells, probably both by passive & facilitated diffusions

  9. Reversibly bind to 50S-ribosomal subunit Prevent the action of peptidyl transferase enzyme Interference with transfer of elongating polypeptide chain in the nearly attached amino-acyl tRNA at ribosome-mRNA complex

  10. Bacterial resistance Production of Chloramphenicol acetyltransferase enzyme in bacteria Lower affinity of bacterial ribosomes to amphenicols

  11. Pharmacokinetics Highly lipid soluble drugs Efficiently absorbed after oral administration but not in case of ruminants Reduction of p-nitrophenyl group by ruminal microflora

  12. Achieve high levels in most body tissues & fluids including CSF, brain, aqueous humor, placenta & synovial fluid Peak concentration in CSF is almost half of the plasma concentration Eliminated by hepatic metabolism via glucoronide conjugation

  13. Half life of Chloramphenicol Ponnies <1 hour Dogs 1-5 hours Cats 4-8 hours

  14. Antimicrobial spectrum Effective against many aerobic & anaerobic gram positive and gram negative bacteria Have no or less activity against many Strains of Pseudomonas & Proteus Mycobacteria, protozoa, fungi & viruses are resistant to amphenicols

  15. Clinical uses Chloramphenicol: • Chronic respiratory infections • Otitis externa • Typhoid • Brucellosis • Bacterial meningitis • Ocular infections

  16. Florfenicol: Developed for use in animals Recommended mainly in cattle Bovine respiratory diseases associated with Pasteurella hemolytica, Pasteurella multocida (e.g., hemorrhagic septicemia) and Haemophilus somnus

  17. Adverse effects Low order of toxicity in domestic animals when used in recommended doses • Bone marrow suppression (mylosuppression) • Malabsorption syndrome • Gray-baby syndrome

  18. Bone marrow suppression (mylosuppression) Reversible mylosuppression occurs due to inhibition of mammalian mitochondrial protein synthesis in the bone marrow Irreversible mylosuppression results from the formation of toxic metabolites associated with p-nitrophenyl group

  19. Signs of mylosuppression: Lymphopenia Neutropenia Aplastic anemia Pancytopenia

  20. Malabsorption syndrome: Occurs in neonatal calves Disruption of small intestine enterocytes Characterized by enteritis, diarrhea & progressive dehydration

  21. Gray-baby syndrome: Observed in human neonates & infants Accumulation of unconjugated drug Blockage of ETS in liver, myocardium & skeletal muscles Characterized by vomiting, hypothermia, cynosis, cardiovascular collapse & death

  22. Contraindications • Patients with pre-existing hematological disorder • Human neonates & infants • Young calves

  23. Drug interactions • Anticonvulsant drugs like Phenytoin, Primidone and Phenobarbitone • Cyclophosphamide • Macrolides and Lincosamides • β-lactams and Aminoglycosides

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