Pharmacology of AMINOGLYCOSIDES by veterinarian008


									   Chapter-8 (Aminoglycosides)                                  Lecture Notes (PHRM-501), CVAS, Jhang

         Aminoglycosides (Aminocylitols) are a group of natural and semi-synthetic antibiotics
         having amino sugars linked to an aminocyclitol ring by glycosidic bond.
         Streptomycin was the first member of amino glycoside antibiotics discovered in 1944 by
         Walks man and co-workers from a strain of Streptomyces griseus.
         Chemistry and source.
         The aminoglycosides consist of two or more amino sugars joined in glycosidec linkages
         to a hexose (aminogyclitol) nucleus.The presence of amino group on the glycosides and
         the hydroxyl group on the sugars provide high water solubility ( or poor lipid solubility)
         to the drugs. Aminogly- cosides prepared from Streptomyces carry the suffix-mycin,
         where those derived from Micromonospora have name ending with –micin.
  a)      They are water soluble and polar compounds and generally ionize in solution.
  b)      They are not absorbed orally,
  c)      They are bactericidal in action and are more active against gram – negative.
  d)      They are more active in alkaline pH.
  e)      They show synergistic antibacterial effect with beta – lactam antibiotics,
         On the basis of antibacterial spectrum, amino glycosides may be classified into following
  I.      Narrow-spectrum aminnoglycosides
         e.g., streptomycin and dihydrostreptomycin.
             II.     Broad-spectrum amino glycosides.
                      E.g., neomycin, framycetin,kanamycin and paromomycin.
         Mechanism of action
                  The amino glycosides are bactericidal drugs that act by inhibiting protein
         synthesis in susceptible bacteria, mainly gram – negative organisms.

         2.      Binding of amino glycosides to bacterial ribosomes.
                 Amino glycosides can bind with both 30 S and 50 S ribosomal subunits, although
         their binding with 30 S subunit is stronger.
  b)      Distortion of m-RNA Condon resulting in misreading of the codon. This causes
         incorporation of one or more incorrect amino acid (s) into peptide chain and synthesis of
         abnormal proteins.
  c)      Promotion of premature termination of translation with detachment of the ribosomal
         complex. Binding of aminoglycosides to 30 S- 50 S juncture is probably responsible for
         their bactericidal effect,
  iii)     Aminoglycosides show long and concentration dependent post – antibiotic effect. There
         fore , despite their short half – lives a single injection of the total daily dose of
         aminoglycosides may be effective.

         Antibacterial Spectrum
         Antibacterial spectrum of aminoglycosides varies with the type of antibiotic streptomycin
         and dihydrostreptomycin have relatively narrow spectra mainly gram-negative species.
         The broad-spectrum aminoglycosides(e.g. neomycin and kanamycin) are active against
         many gram-negative and gram-positive organisms,
         But not pseudomonas. The extended-spectrum aminoglycosides posses antibacterial
         spectra similar to broad-spectrum antibiotics and are also active against pseudomonas
         aeroginosa and a verity of aerobic bacteria. Anaerobic bacteria are only moderately
         sensitive to aminoglycosides .
         Side effects /Adverse effects
         All aminoglycosides have potential to produce toxic effects, but the relative propensity
         differs . Nephrotoxicity, ototoxicity, and neuromuscular blockade are important adverse
         effects observed with aminoglycosides.

Dr. Muhammad Adil                                 Page 1                                      8/31/2011
   Chapter-8 (Aminoglycosides)                                 Lecture Notes (PHRM-501), CVAS, Jhang
         1. Nephrotoxicity: Nephrotoxicity with aminoglycosides occurs as a result of
         excessive accumulation of antibiotics by the proximal tubular cells in kidneys. As
         aminoglycosides are positively charged agents , they get attracted to negatively charged
         phospholipids of the renal membrane followed by their transport onside the tubular cells
         via pinocytosis. This transport is directly related to the membrane content of phosphatidly
         inositol, which is high in renal cortex and cochlear tissues.
         Manifestations of nephrotoxicity include presence of enzymes of brush border urine,
         proteinurea, presecnces of casts, and low GFR.Aminoglycosides , neomycin is most
         Nephrotoxicity of aminoglycosides can be prevented or minimized by following some
         simple steps like avoiding use of potentially nephorotoxic aminoglycosides , ensuring
         adequate hydration status of patient, and avoiding concurrent use of other nephrotoxic
         2. Ototoxivity:         Aminoglycosides get accumulated into perilymph and endolymph
         of the inner ear in dose and time dependent manner.Ototoxicity is greater when the
         plasma concentration of drug is persistently high. Ototoxicity once occur is usually
         irreversible and result from progressive destruction of vestibular or cochlear sensory
         cells. Vestibular injury leads to nystagmus, in coordination, vertigo, head tilt,ataxia,and
         loss of righting reflex in animal. Hearing impairment or deafness may be produced by
         permanent damage and loss of hair cells in the organ of Corti .Aminoglycosides should
         not be instilled into ear unless the tympanic membrane is intact because direct
         administration of aminoglycosides into the inner ear could cause potential damage.
         3. Neuromuscular blockade:                     All amino-glycosides have potential to
         produce neuromuscular blockade with curare-like action. The effect is produced mainly
         by interference with acetylcholine release from motor nerve endings, probably by
         antagonism of Ca ++ that is normally required for exocytosis.However, concomitant
         administration of neuromuscular blocking agents and general anesthetics with
         aminoglycosides may substantially increase the risk of neuromuscular blockade .
         Contraindications and precautions
             Pre-existing renal disease. Aminoglycosides may impair neuromuscular transmission
         and so are not given to animals with myasthenia gravis. They cause adverse effects on
         fetus, so their use during pregnancy is not recommended unless considered mandatory.
         Drug interactions
                   Aminoglycosides show interaction with drugs that cause ototxicity ,
         nephrotoxicity and neurotoxicity , Concurrent use of aminoglycosides with loop diuretics
         ( e.g.,, frusemide and osmotic diuretics (e.g., mannitol ) may aggravate the nephrototoxic
         or ototoxic effects of aminoglycosides. Risk of neuromuscular blockade and respiratory
         paralysis increases when aminoglysosides are used with inhalant anesthetics or
         neuromuscular blocking drugs .

         Clinical uses
         Septicamemia, osteoarthritis, and mastits.endometritis.
         Side effect/Adverse effects
         Adverse effects of streptomycin are similar to other aminoglycosides antibiotics, but it is
         less nephrotoxic than many aminoglycosides .Hypersensitivity reaction are rare.
         Tetracyclines are a group of broad – spectrum antibiotics having a nucleus of four cyclic
         The first member of the group was chlortetracycline derived from soil actinomycete
         Streptomyces aureofaciens introduced in 1948.
         Chemistry and properties
         As a group, tetracyclines are acidic and hygroscopoic compounds. They chatacteristically
         fluorescence when exposed to ultraviolet light. Physical and chemical properties of
         tetracyclines permit them to be formulated as infection, boluses capsules, powders, feed
         additives, and ointments for veterinary use.
Dr. Muhammad Adil                                 Page 2                                     8/31/2011
   Chapter-8 (Aminoglycosides)                                    Lecture Notes (PHRM-501), CVAS, Jhang
          Tetracyclines are classified according to their duration of action.
         I.      Short-acting tetracyclines(t1/2=<8houres)
                 Oxytetracycline, tetracycline and chlortetracycline.
         II     Intermediate acting tetracycline’s(t1/2=8-16houres)
                Demeclocycline and methacycline.
         III Long-acting tetracyclines (t1/2=<16houres)
                Doxycycline and minocycline.
         Mechanism of action
                  Tetracyclines inhibit bacterial protein synthesis and are primarily bacteriostatic.

         Antimicrobial spectrum
                 The tetracyclines are broad – spectrum antibiotics. They ate active against a wide
         range of aerobic and anaerobic gram- positive and gram-negative bacteria. They are also
         active against Mycoplasma Rickettsia, Chlamydia, and some protozoa like anplasma,
         haemobartonella, and amoebae, Presently strains of pseudomonas aeruginosa, Proteus,
         Serratia, Klebsilla, Salmonella , staphylococcus, and
         corynaebacterium species appear to have become resistant to tetracyclines. Tetracyclines
         are infective against fungi and viruses.
         Effect on bones /teeth: Tetracyclines are deposited in growing teeth and bones
         due to their chelating properties with calcium .They from tetracycline – calcium
         orthophosphate complex, which inhibits calcification e.g. hypoplastic dental enamel and
         results in permanent discoloration (first yellowish) then brownish of the teeth. The
         stained and hypoplastic teeth are more prone to various degeneration. Delay fracture
         healing. Pregnancy in neonates.Tetracyclin may cause temporary suppression.
         Hepatotoxicity: Tetracyclines in excessive doses can produce fatty in flirtation of
         liver.Hepatotoxicity with jaundice due to large doses of tetracyclines has been reported in
         pregnant woman and in some animals

         Contraindication and precautions
         Tetracyclines are contraindicated in hepatic insufficiency,
         Drug interaction
         Antacids decrease the absorption of tetracycline’s from GI tract.

         Clinical uses:        Used for treating mycoplasma , chlamydiae and rickettsiae,
         anaplasma, hemobratonella, ehrlichia, and borrelia, In birds, they are used in the
         treatment of psittacosis. For treating bronchopneumonia, metritis, mastitis, pyodermatitis.
         Tetracyclines may be administered by oral, parenteral , topical, or intramammary route,
         The choice of route of administration depends on the species involved , type of action
         desired and compound to be used,

Dr. Muhammad Adil                                   Page 3                                      8/31/2011

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