AMINOGLYCOSIDES

1. AMINOGLYCOSIDES

2. A group of natural and semi-synthetic antibiotics Discovery of 1st Aminoglycoside (Streptomycin) by Waksman and his co-workers in 1944 from a strain of Streptomyces griseus. Have amino sugars linked to an aminocyclitol ring by means of glycosidic bond

3. Presence of amino group on the glycosides imparts alkaline nature to Aminoglycosides Hydro-oxyl groups on the sugars provide high water Solubility Removal of hydro-oxyl groups (e.g., in Tobramycin) makes the drug more active

4. Aminoglycosides prepared from Streptomyces carry the suffix –mycin Whereas those derived from Micromonospora have their names ending with –micin Bactericidal drugs Inhibitors of bacterial protein synthesis Concentration-dependent antimicrobial action

5. Mode of action

6. Diffusion across the aqueous porin channels of gram negative bacteria to reach periplasmic space • Transportation from periplasmic space into bacterial cytoplasm via an oxygen-dependent process • Resitance of anaerobic bacteria • Binding to 30S-50S ribosomal juncture

7. Aminoglycosides impair the bacterial protein synthesis through several mechanisms including: (a) Interference with the formation of initiation complex. (b) Distortion of mRNA codons resulting in misreading of the codons (c) Premature termination of translation

9. Antibacterial Spectrum • More active against gram negative bacteria • Anaerobic bacteria are resistant to aminoglycosides • Narrow spectrum aminoglycosides: Effective against gram negative bacteria

10. Broad spectrum aminoglycosides: Active against many gram-negative and gram positive organisms but not pseudomonas • Extended-spectrum aminoglycosides: Effective against gram-negative & gram positive bacteria as well as pseudomonas

11. Pharmacokinetics • Water soluble and polar compounds • Do not absorb orally & distribute only extracellularly • More active in alkaline medium • Accumulated in high concentrations in inner ear & renal tubular cells

12. Excluded from brain, CSF, eye • Can cross the placental barrier • Low renal clearance in neonatal animals • Increased renal clearance in dehydrated animals • Only slightly metabolized in the body • Possess a significant post-antibiotic effect

13. Clinical uses Streptomycin is combined with penicillin to treat shipping fever, foot rot & coliform infections Neomycin is used orally or in enema form to treat hepatic encephalopathy Kanamycin is orally used to treat gram negative enteric infections Gentamicin is the most widely used Aminoglycoside to treat local and systemic infections caused by susceptible bacteria

14. Adverse effects Nephrotoxicity: Get attracted to negatively charged phospholipids Excessively accumulated in the proximal tubular cells Inhibit various essential enzymes like phospholipases Reduced synthesis of prostaglandins Proteinuria, presence of casts in urine and low GFR

15. Ototoxicity: Aminoglycosides get accumulated into perilymph and endolymph of the inner ear Ototoxicity once occur is usually irreversible Progressive destruction of vestibular or cochlear sensory cells Hearing impairment or deafness may be produced Vestibular injury leads to nystagmus, inco-ordination, vertigo, head tilt, ataxia & loss of righting reflex

16. Neuromuscular blockade: Interference with the release of acetylcholine from motor nerve endings, probably by antagonism of Calcium Contraindications: • Pre-existing renal disorder • Myasthenia gravis • Pregnancy

17. Drug interactions • Concomitant use of Aminoglycosides with loop diuretics • Co-administration of Aminoglycosides with inhalant anesthetics or neuromuscular blocking drugs • Concurrent use of Aminoglycosides with β-lactam antibiotics

18. TETRACYCLINES

19. Possess a nucleus of four cyclic rings Obtained either naturally or prepared semi-synthetically Chlortetracycline (1st tetracycline) derived from Streptomyces aureofaciens --------------- 1948 Removal of chlorine atom from Chlortetracycline produced semi-synthetic Tetracycline ----------1952

20. They are acidic, amphoteric & hygroscopic compounds Characteristically fluorescence when exposed to UV light Form insoluble chelates with divalent and trivalent cations like Ca+2, Mg+2, Fe+3 and Al+3 Formulated as injections, capsules, powders, feed additives and ointments

22. Mode of action Tetracyclines enter gram negative bacteria by two transport mechanisms passive diffusion through the hydrophilic channels energy-dependent active transport system bind to 30S-ribosomal subunit prevent access of amino-acyl tRNA to acceptor (A) site on the mRNA-ribosome complex

23. This prevents addition of amino acids to the growing peptide chain Reversible inhibition of bacterial protein synthesis Bacteriostatic action At high concentrations they also tend to impair protein synthesis in host cells

25. Pharmacokinetics Absorption of Tetracyclines is variable older drugs (e.g., Chlortetracycline) being less bioavailable recent lipid soluble Tetracyclines (Minocycline & Doxycycline) being 100% bioavailable Oral absorption is retarded by polyvalent cations (Ca+2, Mg+2, Fe+3 & Al+3) that are present in food, milk and milk products

26. Addition of Procaine to Tetracycline solution for I/M administration in small animals to avoid tissue irritation Can cross the placental barrier but not BBB (except Minocycline and Doxycycline) Incorporated into forming bones, enamel and dentine of unerupted teeth Trivially metabolized Excretion: 60% excretion occurs via glomerular filtration pathway 40% excretion occurs via biliary system

27. Antimicrobial spectrum Tetracyclines are broad spectrum, bacteriostaic antibiotics Susceptible organisms: aerobic & anerobic gram positive and gram negative bacteria, rickettisiae & spirocheates Resistant organisms: Pseudomonas, Proteus, Klebsiella, Salmonella, Staphylococcus,Corynebacterium, fungi and viruses

28. Clinical uses • Actinobacillosis (wooden tongue) • Actinomycosis (lumpy jaw ) • Mastitis • Metritis • Pneumonia • Tularemia • Brucellosis • Fowl cholera (Pasteurella multocida) • Psittacosis (also known as chlamydiosis)

29. Anaplasmosis • Ehrlichiosis • Q fever (caused by Coxiella burnetti) • Canine leptospirosis • Avian spirocheatosis (caused by Borrelia anserina) • Lyme disease (caused by Borrelia burgdorferi) • Chlortetracycline is used in food-producing animals as a growth promoter. • Occasionally used as markers for the diagnosis of bone tumors

30. Adverse effects Tetracyclines have a relatively low toxicity at normal dosage levels 1. Gastrointestinal upsets: • Manifested by diarrhea and abdominal pain • Superinfection by non-susceptible pathogens such as fungi, yeast and resistant bacteria • Oral administration of Tetracyclines may cause fatal diarrhea in horses and indigestion in ruminants

31. 2. Effects on bones and teeth: • Tetracyclines are deposited in growing teeth & bones • Form Tetracycline-Calcium-orthophosphate complex which inhibits calcification • Interfere with Calcium deposition in bones and delay fracture healing • May cause temporary suppression of odontogenesis & osteogenesis.

33. 3. Cardiovascular effects: • Rapid I/V administration of Tetracyclines • Rapid chelation of blood Calcium by the Tetracyclines • May result in hypotension, collapse and sudden death • Pre-treatment with Calcium borogluconate • Slow rate of I/V injection 4. Hepatotoxicity: Tetracyclines can produce fatty liver infiltration leading to hepatotoxicity and jaundice

34. Contraindications: • Pregnancy • Infancy • Oral administration to horses & ruminants Drug interactions: • Concurrent administration of Tetracyclines with milk and milk products • Antacids, Iron preparations, Saline purgatives • Kaolin, Pectin & Sodium bicarbonate