Pharm.

Fabs Amaechina

AMINOGLYCOSIDES

Aminoglycosides are a group of bactericidal protein synthesis inhibitors that have broad
spectrum of activity against a wide range of aerobic G -ve and selected G +ve organisms.
They are highly polar, water soluble and polycations, compounds that consist of an amino
sugar coupled in a glycosidic bond with a hexose ring. Almost all the aminoglycosides are
isolated from natural source. They have very poor pharmacokinetic. They include:

1. Streptomycin which was isolated from streptomyces griseus. This showed a great
activity against a wide range of G-ve and G+ve organisms, especially aerobic cocci.
However, its used clinically has been limited to the treatment of mycobacterium
infection due to it high level of toxicity.
2. Neomycin, isolated from Streptomyces fradiae. Neomycin is very active against a
wide range of organisms, but its toxicity has limited its use to mainly topical
application or for local sterilization of the gastrointestinal tract. Kanamycin was
isolated from Streptomyces kanamyceticus. The toxicity of this compound and the
emergence of resistance strains of bacteria has limited the clinical usefulness of
kanamycin.
3. Gentamicin and netilmicin were isolated from actinomytes micromonospora.
4. Tobramycin has the same spectrum of activity with gentamicin, it was isolated from
Streptomyces temerarious.
5. Amikacin and netilmicin are semisynthetic aminoglycosides. Amikacin is derivative
of kanamycin, while neltimicin is derived from sisomicin.

Mechanism of action.
Aminoglycosides are rapidly bactericidal and demonstrate post antibiotic effect. Bacteria
killing are concentration dependent and persist even after the serum concentration has fallen
below the MIC level.
Aminoglycosides diffuse passively through the porins of the bacterial cell wall and are
transported by oxygen dependent active process into the bacterial cytoplasm. Three main
mechanisms have been proposed to be responsible for the bactericidal effect of
aminoglycosides.
a. Aminoglycosides inhibit protein synthesis by binding to the 30s ribosomal subunits of
the bacteria RNA.
b. They induce misreading of the mRNA, leading to the incorporation of the wrong
amino acid into the peptide chain to form aberrant proteins.
c. They induce disruption of the bacterial cytoplasm possibly by the incorporated
aberrant proteins.
The oxygen dependent transport of aminoglycosides is the rate limiting step to antibacterial
effect, and can be inhibited by chloramphenicol, polyvalent cations, anaerobic condition and
acid environment like is obtain during abscess.

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Pharmacokinetic
The aminoglycosides are highly polar compounds that dissociate completely and are
therefore poorly absorbed after oral administration. However, ulceration of the stomach,
inflammation and bowel disease has been shown to enhance absorption of aminoglycosides
after oral administration. Intramuscularly administered dose of aminoglycosides are well
absorbed, reaching peak plasma concentration between 30 – 90minutes. Aminoglycosides
are poorly distributed to most body tissues and cells due to their polar nature. They are
however found in high concentration in the renal cortex and the endolymph and perilymph of
the inner ear and cochlear. Aminoglycosides obviously do not cross the blood brain barrier,
but significantly permeate the placenta barrier. They also penetrate the vitreous humour of the
eyes. Aminoglycosides are eliminated almost entirely through the kidney. About 1005 of the
administered is recovered from the urine after the third day of commencement of therapy.
The half live is between 2-3hours.

Resistance to aminoglycosides
Resistance to aminoglycoside has developed over the years, creating a great need for its
combination with other compatible antibacterial agents to achieve therapeutic results, while
taking cognisance of the toxicity profile of this group of antibacterial agents. The modes of
resistance to aminoglycosides are discussed below.
1. Microorganisms could develop potent transferase enzyme to inactivate
aminoglycosides, through the process of adenylation, acetylation or phosphorylation.
By and large, this is the most clinically important resistance to aminoglycosides
because it prevents binding to the bacterial ribosomes.
2. Naturally, resistance to aminoglycosides may occur due to the failure of the antibiotic
to penetrate the bacterial inner membrane of the cytoplasm. It is important to recall
that tansmembrane movement of aminoglycoside is energy dependent oxygen process
and consequently, anaerobic organisms would be resistant to aminoglycosides.
Resistance is further enhanced by anaerobic condition in normally sensitive
organisms.
3. Conditions that generate acidity, such as abscess would impart resistance to
aminoglycosides.

Toxicity of aminoglycosides

Aminoglycosides can produce both reversible and irreversible vestibular, cochlear, and renal
toxicity.
 Aminoglycosides progressively accumulate in the inner ear and will produce toxicity
in patients that have persistently elevated plasma concentration. Ototoxicity is largely
irreversible and results from progressive destruction of vestibular or cochlear sensory
cells, which are highly sensitive to damage by aminoglycosides. There is usually
combined toxicity when an aminoglycoside is co administered with loop diuretics
such as furosemide and ethacrynic acid.
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  Approximately 8–26% of patients who receive an aminoglycoside for more than
several days will develop mild renal impairment that almost always is reversible. The
most nephrotoxic aminoglycosides are neomycin, gentamicin, and tobramycin. The
toxicity results from accumulation and retention of aminoglycoside in the proximal
tubular cells. The initial manifestation is excretion of enzymes of the renal tubular
brush border, followed by a defect in renal concentrating ability, mild proteinuria, and
the appearance of hyaline and granular casts.
The glomerular filtration rate is reduced after several additional days.

 Look up the clinical uses of aminoglycosides.

Macrolides
Macrolides antibacterial agents are made up of large membered lactone rings, to which are
attached one or two deoxy sugars. These are essentially bacteriostatic protein
synthesis-inhibiting antibacterial agents.
The first member of this group is erythromycin which is a naturally occurring metabolite
isolated from Streptomyces venezualea. The other members, clarithromycin and
azithromycin are semi-synthetic. Clarithromycin differs from erythromycin by the
methylation of the hydroxyl group, while azithromycin is an erythromycin in which the
methyl group has been substituted with a nitrogen atom in the basic lactone ring.

Mechanism of Action and spectrum of activity

The macrolides are bacteriostatic antibacterial agents that bind to the 50 s-ribosomal subunit to
inhibit the translocation process in bacterial protein synthesis. Other drugs like
chloramphenicol and clindamycin have been found to bind to the same binding site and are
likely to be displaced by the macrolides, especially erythromycin a very good example of
antagonistic drug/drug interaction.
Erythromycin is sharing the same spectrum of antibacterial activity with the penicillin and
has been proven to be safe alternative to penicillin sensitive-patients. Erythromycin is active
against G+ve and spirochaetes organisms, but not against G-ve organisms. It is however very
active against N. gonorrhoea.
Clarithromycin is active against G-ve organisms, and its metabolite is twice as active against
H. influenza as the parent drug. Azithromycin is less active against G+ve organisms than
erythromycin, but very active against H. influenza and legionella disease.

*Pharmacokinetic
Erythromycin is incompletely absorbed after oral administration. The drug is highly
susceptible to inactivation by gastric acids, so it is formulated either as enteric coated tablet
or as capsule in enteric coated granules. Food tends to increase gastric acidity, and therefore
delays the absorption of the drug. Erythromycin is better administered before meals. It
distributes well into all tissues and intracellular fluids reaching all sites, except the
cerebrospinal fluids and the brain.

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Clarithromycin is rapidly and well absorbed after oral administration but suffers extensive
first pass effect which tends to reduce the bioavailability drastically by almost 50% or more.
Azithromycin is well absorbed after oral administration. Antacids tend to decrease the peak
plasma concentration of azithromycin.
Macrolides have variable protein binding capacity. Erythromycin and clarithromycin have
about 70-80% protein binding, while azithromycin has very low protein binding capacity
about 5% which is also concentration dependent, decreasing as the tissue concentration
increases.
Erythromycin is excreted in active form in the urine and bile, with plasma elimination half-
life of about 1.6hours. Clarithromycin is metabolised to various active metabolites in the liver
which are excreted by renal or the non-renal routes like the bile. Azithromycin is metabolised
in the liver to some inactive metabolites which are excreted unchanged in the urine. The drug
has a half-life that ranges between 40-68 hours.

*Look up
 The antibacterial profile and uses of the macrolides.
 Chloramphenicol: Its MOA, Pcokinetic, Uses and toxicity, especially the grey baby
syndrome.