2. Antibiotics - Aminoglycosides Pharmacognosy IV PHG 423 Dr/ Abdulaziz Saeedan Pharmacy College 1

Aminoglycosides bactericidal bacterialprotein Gram-negative  Aminoglycosides are a group of bactericidal antibiotics that inhibit the synthesis of bacterial protein and are particularly active against Gram-negative bacteria.  Most of aminoglycosides are natural compounds, while other members are produced semi-synthetically.  Streptomycin is the first aminoglycoside antibiotic to be discovered (1943) and was the first antibiotic to be used in treatment of tuberculosis.

Common features  Aminoglycosides are polar compounds (water soluble).  They are poorly absorbed after oral administration.  They have excellent activity against aerobic gram-negative bacilli.  They are bactericidal in action.  All inhibits protein synthesis  They show synergistic antibacterial effect with beta-lactam antibiotics.  They are ototoxic and nephrotoxic (due to prolonged use).

Aminoglycosides: Classification  Aminoglycosides are classified according to the producing microorganisms into: 1- Aminoglycosides obtained from Micromonospora spp. o Gentamicin (gentamicin, sisomicin and netilmicin) 2- Aminoglycosides obtained from Streptomyces spp. o Streptomycin (streptomycin & dihydrostreptomycin) o Kanamycin (kanamycin, amikacin & tobramycin) o Neomycin NOTE:  Aminoglycosides that are isolated from Micromonospora genus are named with a terminal -micin, while those which are isolated from Streptomyces are named with a terminal -mycin.

 Aminoglycosides are classified according to spectrum into: 1- Narrow-Spectrum Aminoglycosides o Ex- streptomycin and dihydrostreptomycin.  They are active against aerobic, gram-negative bacteria including Enterobacteriaceae (E. coli, Salmonella, Klebsiella, Proteus).  Streptomycin acts also against Mycobacterium tuberculosis. 2- Broad-Spectrum Aminoglycosides o Ex- neomycin & kanamycin.  They are active against aerobic, gram-negative bacteria and some gram-positive organisms (Staphylococci & Streptococci), but not Pseudomonas. 3- Expanded-Spectrum Aminoglycosides o Ex- gentamicin, sisomicin, netilmicin, tobramycin & amikacin.  Their antibacterial activity is similar to broad-spectrum aminoglycosides in addition to Pseudomonas.NOTE:  Aminoglycosides are mostly ineffective against anaerobic bacteria.

Aminoglycosides: Pharmacokinetics 1- Absorption o Oral:  Aminoglycosides are highly polar compounds so poorly absorbed from the healthy GI tract (about 3%).  Because only about 3% of an orally administered dose is absorbed from the GIT, Aminoglycosides are usually administered parenterally (injection) or topical. NOTES:  Oral administration can be used for gut decontamination (e.g. in hepatic encephalopathy).  Hepatic encephalopathy  Hepatic encephalopathy is a brain disorder, and one of the major complications of cirrhosis. hepatic coma  In the advanced stages it is called hepatic coma that may lead to death.  Hepatic encephalopathy occurs when the liver is damaged and cannot remove toxic chemicals from the blood, such as bacterial toxins and ammonia. These chemicals then enter the brain and affect both the mental and physical condition of cirrhotic patients.  Oral aminoglycosides are used to suppress bacteria in the intestines that may release toxins.

o Injections:  Given by I/M or I/V injections for systemic effects.  I/M absorption is good.  I/V administration should occur over at least 30 to 60 minutes. NOTE: Because beta-lactam antibiotics inactivate aminoglycosides in vitro, they should not be mixed in the same solution. o Topical:  Some aminoglycosides (Neomycin) are used in topical preparations for wounds.

2- Distribution  Aminoglycosides are polar compounds, so they are distribute to extracellular fluids with minimal penetration into most tissues (limited tissue penetration). o Penetration into CNS is poor (They cross the BBB in children but not in adults). o Do not penetrate into milk. o May cross the placenta. Exceptions (sites of accumulation):  Relatively high concentrations of aminoglycosides are found only in the renal cortex of the kidneys and the endolymph of the inner ear.

3- Elimination  Aminoglycosides are excreted unchanged in the urine.  Approximately 99 % of the injected dose is eliminated unchanged in the urine mainly by glomerular filtration, therefore concentrations in the urine may reach more than 10 times those in the serum.  Impaired renal function reduces the rate of excretion and may lead to accumulation of aminoglycosides in the renal cortex and inner ear tissues causing nephrotoxicity, ototoxicity or both.

Antimicrobial spectrum  Antibacterial spectrum of aminoglycosides varies with the type of antibiotic. aerobic, gram-negative  All aminoglycosides are active against aerobic, gram-negative bacteria.  Anaerobic bacteria are resistant. OXYGEN  Aminoglycosides are transported across the bacterial membrane into cytoplasm by an OXYGEN dependent actively transport process. Therefore they have no activity against anaerobic bacteria.

Action & Mechanism of action  Aminoglycosides have bactericidal activity.  The main site of action of aminoglycosides is the bacterial ribosomes through which they interfere with protein synthesis.  Aminoglycosides bind to the 30S ribosome causing misreading of mRNA so interfere with the process of amino acids polymerization and result in synthesis of non-functional or defective protein.  Defective protein fails to function correctly.

TOXICITY  All aminoglycosides have potential to produce toxic effects.  Ototoxicity and nephrotoxicity are the most important toxic effects observed with aminoglycosides. 1- OTOTOXICITY:  Ototoxicity is the damage of both cochlear and vestibular division of the 8 th cranial nerve (the nerve that is responsible for hearing and balance).  Ototoxicity affects both hearing (cochlea) and balance (vestibule) functions of the ear.

Ototoxicity can be divided into: 1- Cochlear toxicity OR Cochleotoxicity  Occurs due to damage of the cochlear branch of the 8 th cranial nerve that is responsible for hearing.  Symptoms range from mild tinnitus (ringing in the ears) to total hearing loss.  Cochlear toxicity can include one-sided or two-sided hearing loss. 2- Vestibular toxicity OR Vestibulotoxicity  Occurs due to damage of the vestibular branch of the 8 th cranial nerve that is responsible for balance. The symptoms typically include vertigo, imbalance and visual symptoms. The visual symptoms occurs only when the head is moving. They include oscillopsia (blurring of vision) and nystagmus (eye jerking).

Risk factors for ototoxicity include: High doses and therapy for more than 7 days. Repeated exposure to aminoglycosides, Increased age. NOTES: o Ototoxicity can be temporary or permanent. o The use of some aminoglycoside (e.g. streptomycin) in pregnant women, especially during the first trimester, may cause ototoxicity and other congenital abnormalities in the fetus.

2- NEPHROTOXICITY  Nephrotoxicity is one of the most important side effects of aminoglycoside antibiotics  The most nephrotoxic aminoglycosides are neomycin, gentamicin and tobramycin.  Nephrotoxicity results from excessive accumulation of aminoglycosides in the proximal tubular cells of the kidneys.  It is usually reversible since proximal tubular cells can regenerate.  Manifestations of nephrotoxicity include proteinuria and presence of casts in the urine.  High serum creatinine level is used as a marker for kidney damage caused by these drugs.

Risk factors for nephrotoxicity include : Prolonged duration of therapy. Concurrent use of other nephrotoxic agents (Amphotericin B, Vancomycin) Recent aminoglycoside therapy Increased age NOTES: Nephrotoxicity is usually reversible. Aminoglycosides are given for short time periods.

CLINICAL USES  Aminoglycosides are excellent agents for infections due to aerobic gram- negative bacteria.  Gentamicin is the most commonly used aminoglycoside.  Amikacin can be particularly effective against resistant organisms.  Tobramycin shows better activity against Pseudomonas aeruginosa. Empirical therapy The primary indication for aminoglycosides is as short-term empirical therapy for serious infections pending the outcome of diagnosis. bactericidal resistance Their value as empirical drugs relates to their rapid bactericidal activity and low level of resistance. When used empirically, no further doses should be given after 48 hours.

Serious infections includes:  Septicemia.  Endocarditis  Peritonitis and other severe intra-abdominal infections  Urinary tract infections  Respiratory tract infections. Other uses:  Mycobacterium infections like TB  Topically for ocular infections, infected burns and wounds. NOTES:  Septicemia  Septicemia (Sepsis - blood infection) is a serious medical condition characterized by presence of bacteria or their toxins in the blood.  Endocarditis  Endocarditis is an inflammation of the inner layer of the heart (the endocardium) including the heart valves due to bacterial growth.

Oral neomycin and streptomycin are used for sterlization of bowel and for dysentery because A.They are least absorbed from oral route - The aminoglycoside that can be used in amoebiasis is Paromomycin - Streptomycin sulfate is not absorbed orally because it is highly ionized at a wide range of pH values Which toxic effect of aminoglycoside antibiotics is most irreversible in nature? Vestibular damage Hearing loss Neuromuscular blockade Kidney damage Which aminoglycoside antibiotic causes more hearing loss than vestibular disturabance as toxic effect ? (a) Streptomycin (b) Gentamicin (c) Kanamycin (d) Sisomicin

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