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Tetracyclines
1. Dr. N. S. MEENA
DEPARTMENT OF VETERINARY PHARMACOLOGY AND
TOXICOLOGY
Post Graduate Institute of Veterinary Education and Research (PGIVER)
(Rajasthan University of Veterinary and Animal Sciences)
N.H. 11, Agra Road, Jamdoli campus, Jaipur – 302031
2. • Tetracyclines are a group of broad-spectrum antibiotics having
a nucleus of four cyclic rings. They are either obtained naturally
from soil actinomycetes or prepared semi-synthetically. They
have similar antimicrobial features, but differ somewhat from
one another in terms of their antimicrobial spectra and
pharmacokinetics.
• The general usefulness of tetracyclines has declined with the
onset of bacterial resistance, but still they remain the
treatment of choice for some specific infections.
TETRACYCLINES
3. History
• Tetracycline antibiotics were produced by systemic screening of
soil microorganisms. The first member of the group was
chlortetracycline derived from soil actinomycete Streptomyces
aureofaciens introduced in 1948. This was followed by
oxytetracycline.
• Removal of chlorine atom from chlortetracycline produced
semi-synthetic tetracycline introduced in 1952.
• Further discovery led to other semi-synthetic tetracyclines like
metacycline, doxycycline and rolitetracycline. Doxycycline and
minocycline are relatively newer tetracyclines with high lipid
solubility and longer duration of action.
• In 2005, tigecycline, the first member of a new subgroup of
tetracyclines named glycylcyclines, was introduced to treat
infections which are resistant to other antimicrobials including
conventional tetracyclines.
4. Chemistry and Properties
• Tetracyclines are close congeners of polycyclic
naphthacenecarboxamide. They are a family of four ringed
amphoteric compounds which differ by specific substitutions at
different points on the rings. As a group, tetracyclines are acidic
and hygroscopic compounds, which in aqueous solution form
salts with both acids and bases.
5. • Tetracyclines are generally classified according to their duration
of action.
I. Short-acting tetracyclines (t1/2 = <8 hours)
e.g. oxytetracycline, tetracycline and chlortetracycline,
II. Intermediate acting tetracyclines (t1/2 = 8-16 hours)
e.g. demeclocycline and metacycline.
III. Long-acting tetracyclines (t1/2 = >16 hours)
e.g. doxycycline, minocycline and tigecycline.
Classification
6. Mechanism of Action
• Tetracyclines inhibit bacterial protein synthesis and are primarily
bacteriostatic.
• The action of tetracyclines can be divided Into two processes-
– Passage of tetracyclines into bacterial cell
– Interaction of tetracyclines with bacterial ribosomes.
7. • Passage of tetracyclines into bacterial cell:
• Tetracyclines enter gram-negative bacteria by two transport
mechanism- in part by a passive process and in part by an
active process. The first is passive diffusion through the
hydrophilic channels formed by the porin proteins in outer
cell membrane. The more lipid soluble membrane (e.
doxycyline and minocycline) pass directly through the lipid
bilayer by passive diffusion
• The second mechanism involves an energy dependent active
transport system that pump all tetracyclines across
cytoplasmic membrane although passage of tetracycline in to
gram-positive bacteria is less well understood it requires an
energy dependent carrier transport mechanism.
8. • Interaction of tetracyclines with bacterial ribosomes:
• Once the tetracyclines gain access to bacterial cell, they bind
to the 30S ribosomal subunit. They prevent binding/ access
of aminoacyl t-RNA to the acceptor (A) site on the m-RNA-
ribosom complex. This prevents addition of amino acid to
growing peptide chain resulting in inhibition of protein
synthesis .
9. • Tetracyclines are highly effective against multiplying
microorganisms and are more active at pH 6-6.5.
• Effects of tetracyclines are mostly reversible as the bacterial
protein synthesis is restored when the drug is removed.
Although the tetracyclines are primarily bacteriostatic, at high
concentrations (e.g. in urine) they tend to become bactericidal
because at high concentrations they appear to affect the
functional integrity of bacterial cell membranes as well.
Moreover, the mammalian protein synthesising apparatus is
less sensitive to tetracyclines.
10. Fig. 1: Bacterial protein synthesis and the site of action of antibiotics
11. Pharmakinetics
• Absorption: The oral absorption of tetracyclines is variable
with older drugs (e.g. chlortetracycline) being less
bioavailable and newer lipid soluble tetracyclines (e.g.
minocycline and (loxycycline) being 100% bioavailable.
Absorption of tetracyclines From GI tract is decreased in
presence of polyvalent cations (e.g. Ca++ Mg++ and Fe+++)
which are present in food, and milk and milk products.
• All tetracyclines produce varying degree of tissue irritation
on parenteral administration, especially chlortetracycline.
'Therefore for parenteral administration, buffered solutions
are prepared. Procaine is added to tetracyclines solution for
IM administration in case of small animals.
12. Distribution
• Tetracyclines bind to plasma proteins to varying degrees and
are widely distributed in most tissues including kidneys, liver,
lungs, bile and bones. However, with exception of lipid soluble
members (e.g. doxycycline and minocycline), tetracyclines do
not penetrate the brain and CSF.
• Tetracyclines are stored in the reticuloendothelial cells of liver,
spleen and bone marrow. They are also incorporated into
forming bone and enamel and dentine of unerupted teeth
possibly because of their binding action with Ca++.
Tetracyclines cross the placenta and enter foetal circulation
and amniotic fluid.
13. Biotransformation and excretion:
• With exception of lipid soluble tetracyclines, the tetracycline
antibiotics are not metabolised to a significant extent in the
body. Most tetracyclines are excreted in urine (60%) via
glomerular filtration pathway and in faeces (40%) via biliary
excretion. Tetracyclines undergo enterohepatic circulation,
which may affect their duration of action.
14. Side Effects/Adverse Effects
• The tetracyclines have a relatively low toxicity at normal
dosage levels. However, a number of side effects have been
associated with tetracyclines. Side effects may be worsened
in animals with renal disease due to decreased elimination
of the drug.
15. Gastrointestinal upsets
• All tetracyclines produce GI irritation to varying degree in
some patients, particularly after oral administration. Anorexia,
abdominal pain, diarrhoea, nausea and vomiting in small
animals may occur.
• Superinfection by non-susceptible pathogens such as fungi,
yeast and resistant bacteria is a possibility, which if occurs may
lead to disturbances in the intestinal function with candidiasis,
enterocolitis or pseudomembranous colitis.
• The oral administration of tetracyclines may lead to fatal
diarrhoea in horses and indigestion due to deleterious effect
on rumen microbes in ruminants.
16. Effect on bones/teeth
• Tetracyclines are deposited in growing teeth and bones due
to their chelating properties with calcium. They form
tetracycline-calcium orthophosphate complex, which inhibits
calcification (e.g. hypoplastic dental enamel) and results in
permanent discolouration (first yellowish then brownish) of
the teeth.
• The stained and hypoplastic teeth are more prone to various
degenerations. High concentrations of tetracyclines can
interfere with the calcium deposition in bones and delay
fracture healing. Given during pregnancy or in neonates,
tetracyclines may cause temporary suppression of bone
growth.
17. • Hepatotoxicity:
Tetracyclines in excessive doses can produce fatty
infiltration of liver. Hepatotoxicity with jaundice due to
large doses of tetracyclines has been reported in pregnant
women and in some animals.
• Nephrotoxicity:
Tetracyclines are potentially nephrotoxic, particularly in
renal insufficiency. They may impair urinary concentrating
ability in patients even with normal renal function.
The administration of expired tetracycline products may
lead to b acute tubular nephrosis in animals. The
inhibition of mammalian protein synthesis has catabolic
effect resulting in increase in the blood urea nitrogen
(BUN).
18. • Hypersensitivity reactions:
Hypersensitivity reactions are not common with tetracyclines.
Rarely, they may produce skin rashes, urticaria, pruritus and
exfoliattve dermatitis. Angioedema and anaphylaxis are
extremely rare. Compelete cross-sensitisation is exhibited by
tetracyclines. Minocycline may be more likely to cause allergic
drug reactions.
• Cardiovascular effects:
The rapid intravenous administration of tetracyclines may
result in hypotension, collapse and sudden death in animals.
This has been related to rapid chelation of blood calcium,
although a depressant effect by propylene glycol carrier itself
may also be involved. Pre-treatment with calcium
borogluconate and slow rate of IV infusion prevent these
unwanted effects.
19. • Other effects:
• Tetracyclines cause irritation on parenteral administration.
Swelling, necrosis and yellow discolouration usually occur at
injection site.
• The tetracyclines inhibit WBC chemotaxis and phagocytosis
at injection sites, particularly when present in high
concentrations.
• Tetracyclines may prolong blood coagulation either directly
by chelating calcium or indirectly by depressing prothrombin
synthesis due to depression of vitamin K by bacterial flora.
• Other adverse effects caused by tetracyclines include drug
fever in cats, photoallergic dermatitis in humans and
antianabolic effect in many species.
20. Clinical Uses
• Although tetracyclines are broad-spectrum antibiotics, they
should be employed only for those infections for which a
more selective and less toxic AMA is not available. Clinical
use of tetracyclines has very much declined due to
availability of fluoroquinolones and other efficacious AMAs.
21. 1.Empirical therapy
• Tetracyclines are often employed when the nature and
sensitivity of the infecting organism cannot be reasonably
guessed, but they are not dependable for empirical
treatment of serious/life-threatening infections.
• They may also be used for initial treatment of mixed
infections, although a combination of β-lactam and an
aminoglycoside antibiotic or a third generation
cephalosporin or a fluoroquinolone are now preferred.
22. 2. Tetracyclines are the first choice drugs:
despite development of resistance by many organisms in:
(a) Venereal diseases:
• Chlamydial nonspecific urethritis/endocervicitis:
7 day doxycycline treatment is as effective as azithromycin
single dose.
• Lymphogranuloma venereum: resolves in 2–3 weeks.
• Granuloma inguinale: due to Calymm. granulomatis: a
tetracycline administered for 3 weeks is the most effective
treatment.
24. 4. Other situations in which tetracyclines may be used are:
(a) Urinary tract infections:
(b) Community-acquired pneumonia, when a more selective
antibiotic cannot be used.
(c) Amoebiasis:.
(d) As adjuvant to quinine or sulfadoxinepyrimethamine for
chloroquine-resistant P. falciparum malaria .
(e) Acne vulgaris:
(f) Chronic obstructive lung disease:
25. Contraindications and Precautions
• Tetracyclines are contraindicated in hepatic insufficiency,
renal diseases and in patients those are hypersensitive to
them.
• Oral administration of tetracyclines to ruminants and horses
is not recommended because they inhibit the normal
bacterial fermentation of plant fibres. They should not be
used in the last 2-3 months of gestation in pregnant animals
and up to 4 weeks in neonates.
26. • Tetracycline preparations should never be used beyond their
expiry date because they cause damage to the proximal
renal tubule due to the formation of a degradation product,
anhydro-4-epitetracycline causing `Fanconi syndrome'.
• In Fanconi syndrome glucose, amino acids, uric acid,
phosphate and bicarbonate are passed into the urine,
instead of being reabsorbed.
27. • Tetracyclines should never be administered with food, milk
and milk products because they bind with food particles and
also easily with magnesium, aluminium, iron and calcium in
food and milk products thereby forming insoluble
complexes, which reduce the absorption ability of
tetracyclin. Therefor oral tetracyclines are generally given at
least 1-2 hours before or after food and milk or any cation
containing product.
• Partial exceptions to these rules occur for doxycycline and
minocycline, which may be taken with food (though not iron,
antacids, or calcium supplements).
• Tetracyclines should not be given intrathecally.
28. AMPHENICOLS
• Amphenicols are a group of broad spectrum bacteriostatic
drugs which function by blocking protien synthesis of
suceptible bacteria.
• These drugs are structurally related and belong to the class
of antibiotics with a phenylpropanoid structure.
• Amphenicols includes chloramphenicol the parent compund
and its congeners thiamphenicol, florfenicol and
azidamfenicols.
29. CHLORAMPHENICOL
• Chloramphenicol was initially obtained from Streptomyces
venezuelae in 1947. It was soon synthesized chemically and the
commercial product now is all synthetic.
• It is a yellowish white crystalline solid, aqueous solution is quite
stable, stands boiling, but needs protection from light.
• It has a nitrobenzene substitution, which is probably
responsible for the antibacterial activity and its intensely bitter
taste.
30. Mechanism of action Chloramphenicol
• Inhibits bacterial protein synthesis by interferring with
‘transfer’ of the elongating peptide chain to the newly
attached aminoacyl-tRNA at the ribosome-mRNA complex.
• It specifically attaches to the 50S ribosome and thus may
hinder the access of aminoacyl-tRNA to the acceptor site for
amino acid incorporation.
• Probably by acting as a peptide analogue, it prevents
formation of peptide bonds.
• At high doses, it can inhibit mammalian mitochondrial
protein synthesis as well. Bone marrow cells are especially
susceptible.
31. Fig. 1: Bacterial protein synthesis and the site of action of antibiotics
32. Antimicrobial spectrum
• Chloramphenicol is primarily bacteriostatic, though high
concentrations have been shown to exert bacteriocidal
effect on some bacteria. It is a broad-spectrum antibiotic,
active against nearly the same range of organisms (gram-
positive and negative bacteria, rickettsiae, mycoplasma) as
tetracyclines
33. Adverse effects
1. Bone marrow depression of all drugs, chloramphenicol is the
most important cause of aplastic anaemia, agranulocytosis,
thrombocytopenia or pancytopenia. Two forms are
recognized:
(a) Non-dose related idiosyncratic reaction: This is rare (1 in
40,000), unpredictable, but serious, often fatal, probably has
a genetic basis and is more common after repeated courses.
Aplastic anaemia is the most common manifestation.
Apparently, a longer latent period of onset of marrow
aplasia is associated with higher mortality. Many victims,
even if they survive, develop leukaemias later.
34. (b) Dose and duration of therapy related myelosuppression: a
direct toxic effect, predictable and probably due to inhibition
of mitochondrial enzyme synthesis. This is often reversible
without long-term sequelae. Liver and kidney disease
predisposes to such toxicity.
35. 2. Hypersensitivity reactions Rashes, fever, atrophicglossitis,
angioedema are infrequent.
3. Irritative effects Nausea, vomiting, diarrhoea, pain on
injection.
4. Superinfections These are similar to tetracyclines, but less
common.
36. 5. Gray baby syndrome
• It occurred when high doses (100 mg/kg) were given
prophylactically to neonates, especially premature. The baby
stopped feeding, vomited, became hypotonic and
hypothermic, abdomen distended, respiration became
irregular; an ashen gray cyanosis developed in many,
followed by cardiovascular collapse and death. Blood lactic
acid was raised. It occurs because of inability of the newborn
to adequately metabolize and excrete chloramphenicol.
• At higher concentration, chloramphenicol blocks electron
transport in the liver, myocardium and skeletal muscle,
resulting in the above symptoms. It should be avoided in
neonates, and even if given, dose should be 25 mg/kg/day.
