Aminoglycosides The Aminoglycosides are used primarily in the

Aminoglycosides

The Aminoglycosides are used primarily in the treatment of infections caused by Gm –ve microorganisms. v The major clinically important aminoglycosides are: - Amikacin - Gentamicin - Kanamycin - Netilmicin - Neomycin - Paromomycin - Streptomycin - Tobramycin v Aminoglycosides which are derived from: - Streptomyces genus are named with the suffix –mycin. - While those which are derived from Micromonospora are named with the suffix –micin.

v Aminoglycosides are so named because their structures consist of amino sugars linked glycosidically. * All have at least one aminohexose * Some have a pentose lacking an amino group (e. g. streptomycin, neomycin and paromomycin). v All are available as sulfates. v They distribute well into most body fluids, but not into the central nervous system, bone, or fatty or connective tissues. v Aminoglycosides tend to concentrate in kidney and are excreted by glomerular filteration.

Physical and chemical properties: Ø They are water-soluble due to their polar groups (hydroxyl and amine groups), stable in solution and more active at alkaline than at acid p. H. Ø Aminoglycosides frequently exhibit synergism with β-lactams or vancomycin. However, aminoglycosides may complex with β-lactam drugs, resulting in loss of activity and they should not be mixed together for administration.

Streptomycin sulfate Neomycin sulfate

Kanamycin sulfate Amikacin

Gentamicin sulfate

Netilmicin sulfate

Spectrum of activity v Aminoglycosides are classified as broad-spectrum antibiotics, they used for treatment of serious systemic infections caused by aerobic Gm –ve bacilli. v Aerobic Gm –ve and Gm +ve cocci (with the exception of Staphylococci) tend to be less sensitive to aminoglycosides and thus the β-lactam and other antibiotics tend to be preferred for the treatment of infections caused by these organisms. Single daily dosing q Single daily doses of aminoglycosides are at least as effective as and no more toxic than multiple daily doses.

THERAPEUTIC USES n Severe , complicated infections. n Often combined with β-lactams.

STREPTOMYCIN n Bacterial endocarditis (combined with a penicillin or vancomycin). n Tuberculosis.

Gentamicin, Tobramycin, Netilmicin and Amikacin n Similar in clinical indications and range of activity. n Gentamicin is often preferred but resistance may limit its use.

THERAPEUTIC USES n Serious gram negative infections especially those due to Pseudomonas, Enterobacter, Klebsiella, Serratia etc. n UTI’s, bacteremia, meningitis, infected burns, pneumonia, osteomyelitis, ear infections etc.

THERAPEUTIC USES n Severe Pseudomonas infections are best treated with one of these 4 AG’s plus an antipseudomonal penicillin or cephalosporin. n Gentamicin combined with a penicillin is often used to treat bacterial endocarditis.

THERAPEUTIC USES n Tobramycin is often used in pseudomonal infections. n Amikacin is used as the preferred agent in hospitals. n Netilmicin- may be useful in resistant infections.

DRUG INTERACTIONS n Antipseudomonal penicillins inactivate aminoglycosides. n Ethacrynic acid and other loop diuretics. n Nephrotoxic agents. n Neuromuscular blocking agents.

THERAPEUTIC USES OF THE AMINOGLYCOSIDES Streptomycin T. B. , Endocarditis Gentamicin Endocarditis, gram negative infections, Pseudomonas Tobramycin Gram negative infections, Pseudomonas Amikacin Reserve drug for gram negativeinfections

Nascent polypeptide chain A 50 S Transferase site aa m. RNA template P 30 S Mechanism of action of Aminoglycosides AG’s

Mature protein Blocks initiation Growing polypeptide 5’ 50 S 3’ 30 S 3’ Premature termination 5’ 5’ AUG Wrong amino acid is incorporated 3’ X 5’ AUG m. RNA translation + aminoglycoside Effects of Aminoglycosides 3’

Aminoglycosides on Protein Synthesis Mature Protein Blocks initiation 5’ Growing Polypeptide 5’ AUG Premature 3’ 50 S 3’ termination 3’ 5’ X 30 S + m. RNA translation Amino Glycoside 5’ Incorporation of wrong amino acid 3’

MECHANISM OF ACTION n Exact mechanism of cell death is unknown. n Postantibiotic effect.

RESISTANCE n Alterations in ribosomal proteins. n Decreased permeability to the antibiotic.

Adverse reaction: 1 - Nephrotoxicity 2 - Ototoxicity 3 - Neurotoxicity 4 - Neuromuscular blockade Additional adverse reactions with administration of aminoglycosides may include: nausea, vomiting, anorexia, rash, and urticaria.

Contraindications: Ø Aminoglycosides should not be given to patients requiring long term therapy because of the potential for ototoxicity and nephrotoxicity. Ø These drugs are contraindicated in patients with: - Preexisting hearing loss - Myasthenia gravis - Parkinsonism - During lactation or pregnancy. Ø The aminoglycosides are used cautiously in patients with renal failure, in the elderly and in patients with neuromuscular disorders.

ABSORPTION AND DISTRIBUTION n Oral bioavailability is low. n Once daily dosing (postantibiotic effect). n Distribution into most body tissues including the CNS is low.

EXCRETION n Rapidly and almost entirely excreted by glomerular filtration (proportional to creatinine clearance) n Accumulation occurs with impaired renal function