Aminoglycosides - 7.Aminoglycosides - Vikram.pptx PDF

Dr.P.Vikrama Chakravarthi, AMINOGLYCOSIDES PhD,PGDEVP Associate Professor Dept.of Vet.Pharmacology and Toxicology VCRI,Udumalpet VIKRAM VPT Introduction  AMINOGLYCOSIDES Natural and semisynthetic antibiotics  Streptomycin – Streptomy...

Dr.P.Vikrama Chakravarthi, AMINOGLYCOSIDES PhD,PGDEVP Associate Professor Dept.of Vet.Pharmacology and Toxicology VCRI,Udumalpet VIKRAM VPT Introduction  AMINOGLYCOSIDES Natural and semisynthetic antibiotics  Streptomycin – Streptomyces griseus First Member -1944 – Waksman & Team  Neomycin, Kanamycin & Gentamicin  Amikacin - Semi-Synthetic drug VIKRAM VPT  AMINOGLYCOSIDES  Aminosugars connected via glycosidic bond linked to aminocyclitol ring COMMON PROPERTIES  Hydrophilic, water soluble (Polar) compounds  Available as water soluble sulphate salts  Very limited oral bioavailability  Readily Ionize – Unable to cross barriers  Aminoglycosides – Less active abscess, Pus & tissue debris  More active in Alkaline Urine VIKRAM VPT  AMINOGLYCOSIDES – COMMON PROPERTIES  More active against Gram negative bacteria  Weak Anaerobic activity  Bactericidal – Depends Concentration - Single large dose. Biphasic mode of cidal effect Killing is biphasic, initial fast killing followed by late slow killing  Post antibiotic effect - Residual cidal effect - Drug concentration below the MIC - Strong and Irreversible binding to ribosomes VIKRAM VPT  CLASSIFICATION Based on antibacterial spectrum 1. Narrow Spectrum aminoglycosides Gram Negative e.g.Streptomycin 2. Broad spectrum aminoglycosides Gram Negative and Gram Positive e.g. Neomycin,Kanamycin 3.Extended spectrum aminoglycosides Gram Negative and Gram Positive & Pseudomonas, Mycoplasma e.g. Gentamicin, Amikacin and Tobramycin VIKRAM VPT  MECHANISM OF ACTION Inhibiting the bacterial protein synthesis Binding to 30S ribosome Two steps 1. Entry of Aminoglycosides into cell Entry across the cell wall - Porin channels to Periplasm Entry across the cell membrane - Periplasm to Cytoplasm - Drug Uptake - Oxygen dependent transport system Anaerobic environment – Inhibits –VIKRAM System VPT –  MECHANISM OF ACTION 2.Drug binding to bacterial ribosomes - 30S subunit a. Interfere with formation of Initiation complex. b. Alteration of m-RNA codon – Misreading of codon Incorporation of incorrect aminoacids - abnormal proteins c. Premature termination of translation Detachment of ribosomal complex – Incomplete Protein Synthesis d. Also inhibit ribosomal translocation - (tRNA movement from A site to P site inhibited) Streptomycin acts in single step. Other drugs severalVIKRAM sites VPT  DRUG RESISTANCE Bacteria develop resistance - Plasmid mediated & Mutation 1. Alteration in Ribosome structure One step mutation e.g.E.coli resistant to Streptomycin 2. Inactivating enzymes Bacteria producing Transferases Nine-Amikacin Resistant 3. Reduced CM penetration/Impaired transport Decreased Pore size/no. in cell wall. Eg.Pseudomonas Advantage - Partial Resistance - Bacteria resistant to streptomycin - VIKRAM VPT  PHARMACOKINETIC S Absorption Oral-Poor absorption (10%) Poultry Industry – Neomycin - Oral Unabsorbed antibiotics - Without inactivation- Enter into Intestine - Bacterial cleansing of intestine. IM-Peak-30-45 Minutes. IV – Also. VIKRAM VPT  PHARMACOKINETIC S Distribution Well distributes in Extra cellular fluids Polar - Not enter- Brain, CSF, body tissue, Except Kidney and Inner ear. Cross Placenta – Deafness in Young ones Biotransformation and Excretion Not completely metabolised, Excreted unchanged - Glomerular filtration Half life - 2 - 4 hrs VIKRAM VPT  SIDE EFFECTS Side effects Nephrotoxicity Ototoxicity Neuromuscular blockade & Allergic reactions 1. Nephrotoxicity Aminoglycosides - Positively charged Renal membrane - Phospholipids - Negatively charged Excess - Accumulated in Proximal tubular cells Enter inside renal tubules - Inhibit Phospholipase - Prostaglandin synthesis - Renal blood flow - GFR Reversible - Initial stages Manifestations - Presence of brush border enzymes in urine, proteinuria, casts and Low GFR, later - Polyuria VIKRAM VPT Neomycin - Most nephrotoxic then tobramycin and gentamicin 2.Ototoxicity SIDE EFFECTS Vestibular and auditory dysfunction - Dose dependent Drug - Accumulated - Perilymph & endolymph - Inner ear - Progressive destruction of Vestibular / Cochlear sensory cells. - So ototoxicity is irreverible, once reported - Vestibular injury - Nystagmus, incoordination, Vertigo in animals / Deafness. Neomycin - Most ototoxic, Streptomycin - Vestibulotoxic Cats - Most affected by ototoxic effect than dogs. 3.Neuromuscular blockade Normally not - With general anaesthetics, Continuous use Aminogly. - By antagonism of Ca (Block exocytosis) - - Inhibit Acetylcholine release in presynaptic site through exocytosis NM Block (Curare like action) - No Contraction - Paralysis of respiratory muscles Treatment - IV Calcium, Neostigmine. Neomycin, Streptomycin - Cause NM Blockade VIKRAM VPT Hence, in Botulism (Also, Ach is blocked) aminoglycosides are  CONTRAINDICATIONS & DRUG INTERACTIONS Contraindications Renal disease Neonates Pregnancy – Not recommended Drug interactions  Synergistic with Betalactam antibiotics- Cell wall injury favours Aminoglycoside uptake Eg.Streptomycin and Penicillin.  Not with Cephalosporins - Additive Nephrotoxic  Also Loop Diuretics (Eg.Furosemide - Ototoxic)  Tubocurarine - NM Block VIKRAM VPT  CLINICAL USES Respiratory tract infections Urinary tract infections GI Tract – Enteritis - Neomycin Osteoarthritis Mastitis Septicemia Wound Eye infection Ear infection. VIKRAM VPT  NARROW SPECTRUM AMINOGLYCOSIDES STREPTOMYCIN - Source - Streptomyces griseus - Spectrum - Aerobic gram negative E.coli, Salmonella,Klebsiella,Pasteurella,Brucella, Campylobacter Mycobacterium tuberculosis - TB - With Isoniazid - Less Nephrotoxic Clinical uses - With Penicillin - Shipping fever, Foot rot, Respiratory tract infections - Dose - Dogs – 5-10 mg/Kg, Cattle,Sheep,Goat VIKRAM VPT – 10  BROAD SPECTRUM AMINOGLYCOSIDES 1. Neomycin Streptomyces fradiae Gram Negative and Gram Positive Major – Oral and Topical Systemic – High toxicity – Not recommended Ototoxicity - Irreversible damage to auditory division of 8th cranial nerve Nephrotoxic Clinical Use Oral - Enteric Infections , Dose – Cattle, Dog & Poultry – 10 mg/kg VIKRAM VPT Topical - Skin,Eye,Ear infections Intramammary – With penicillin  EXTENDED SPECTRUM AMINOGLYCOSIDES Gentamicin Most commonly used – Extended spectrum – Low Cost Micromonospora Purpurea Specific Biological origin – Gentamicin not mycin (Streptomyces) Spectrum Gram negative and gram positive including Staphylococcus Streptococcus, Pseudomonas, Proteus, E.coli & Klebsiella. VIKRAM VPT  EXTENDED SPECTRUM AMINOGLYCOSIDES Gentamicin - Clinical Uses Respiratory tract & Urinary Tract Metritis Mastitis Skin, Eye ,Ear- Topical use Broiler Industry - Dayold chicks - Hatching day - S/C Injection -Early embryonic mortality Pseudomonas infections - Gentamicin Heat stable antibiotic - remain active even after autoclaving - Useful in microbiological media preparation Dose Dog and cat – 5 mg/kg – Once daily Cattle – 2.5 – 5 mg/kg Birds – 5-10 mg/kg. VIKRAM VPT  EXTENDED SPECTRUM AMINOGLYCOSIDES Amikacin  Semi-Synthetic aminoglycoside  Organisms resistant to gentamicin also.  Tuberculosis treatment  Small animals - Dog -Commonly used.  Subclinical avian Mycoplasma infection – Layer and Broiler Industry  Resistant to Drug inactivating enzymes. Dose Dog and cat – 5-10 mg/kg – IM/SC, BID Cattle – 10 mg/kg Birds – 15 mg/kg VIKRAM VPT  EXTENDED SPECTRUM AMINOGLYCOSIDES Tobramycin - Source - Streptomyces tenebrarius - Similar to Gentamicin Sisomicin - Micromonospora inyonensis Netilmicin - Semisynthetic VIKRAM VPT  COMMERCIAL Commercial Preparations PREPARATIONS Veterinary Field - Topmost selling group - Clinical uses/Low Cost -Injection – 2.5 g Injection - Oral – 50 g Streptomycin + Penicillin 100mL Neomycin and Gentamicin Doxycycline powder VIKRAM VPT  SUMMARY AMINOGLYCOSIDES No protein synthesis No lipid solubility No live bacteria (Cidal) No Anaerobic activity Negative (Gram) organisms Side effects - NANO  Nephrotoxicity  Allergy  NM Blockade  Ototoxicity VIKRAM VPT  SUMMARY Aminoglycosides - Mechanism of Action Inhibits protein synthesis by binding to 30S ribosomes VIKRAM VPT  SUMMARY TANGS Tobramycin Amikacin Neomycin Gentamicin Streptomycin Drug Interaction Clinical uses VIKRAM VPT