Post on 05-Apr-2018
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Tetracyclines
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Chemistry
The basic tetracycline structure consists of
four benzene rings with various constituentson each ring.
The crystalline bases are faintly yellow,odorless, slightly bitter compounds. They are
only slightly soluble in water at pH 7 but theycan form soluble sodium salts andhydrochloride.
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Mechanism of Action
The site of action of TET is the bacterial ribosomeand all TET function in the same manner. They arebacteriostatic compounds. They inhibit proteinsynthesis by binding specifically to the 30Sribosome. This appears to prevent access of AA-tRNA to the acceptor site on the mRNA-ribosomecomplex; preventing the addition of AA to the
growing peptide chain.These compounds also impair protein synthesis inmammalian cells at high concentration. For gram (-)bacteria, less understood for gram (+) bacteria.
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Step 1 -Passive diffusion through hydrophilicpores in the outer cell membranes.
Step 2 -Energy-dependent active transportsystem that pumps all TET through the innercytoplasmic membrane.
Minocyline & perhaps doxycycline are morelipophilic than the other TET and pass directlythrough the lipid bilayer.
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Resistance
Resistance to the TET for gram-neg and
gram-pos bacteria is mediated by inducible
plasmid [the bacteria become resistant onlyafter exposure to the drug].
This plasmid mediates the production of a
number of proteins that appear to affect
transport of the drug into the cell, therebypreventing binding to the ribosomes.
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PharmacokineticsAbsorption:
All TET are adequately but incompletelyabsorbed from the G.I. tract. The % of an oraldose that is absorbed (when the stomach isempty) is lowest for chlortetracycline (30%) andhighest for minocycline (~98-100%). Mostabsorption takes place from the stomach andupper small intestine (greater in a fasting state).
Absorption of TET is impaired by food in thestomach, milk products, aluminum OH gels, Na+bicarbonate, Ca++ & Mg++, and Fe++preparations.
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After a single oral dose peak plasma
concentration are achieved in 2-4 hours.
The mechanisms responsible fordecreased absorption for decreased
absorption appear to be chelation and
an increase in gastric pH.
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Distribution
The Vd of the TET is relatively larger thanthat of the body water. They are bound toplasma protein in varying degree.
Penetration of these drugs into most tissuesand body fluids is excellent.
All TET are concentrated in the liver and
excreted by way of the bile into the intestinefrom which they are partially reabsorbed(enterohepatic circulation) Bile: serum ratiorange from 5 lOX that of plasma.
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B. CSF levels are 10 -20% of the serumlevels.
C. TET are stored in the reticuloendothelialcells
D. TET crosses the placental barrier and
can accumulate in fetal bones, thusdelaying bone growth. They are alsoexcreted in breast milk.
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Excretion
All the TET are excreted in the urine and thefeces, the primary route for most being the kidney.The mechanism of renal exertion is glomerularfiltration. They will accumulate in the body inpatients with depressed renal function; EXCEPTdoxycycline -not eliminated via the samepathways as other TET. The drug is excreted in
the feces, largely as an inactive conjugate. Thusone of the safest of the TET for the treatment ofextrarenal infections.
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Adverse Effects
TET can produce a variety of adverse
effects ranging from minorinconvenience to life-threatening.
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Gastrointestinal
TET produce GI irritation to a varying degree in
some but not all individuals. Nausea,
vomiting, burning, diarrhea (common)Diarrhea must be promptly distinguished from
that which results from pseudomembranous
colitis - caused by overgrowth of clostridium
difficile ( can be life-threatening)
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A. Normal -loose stools do not contain blood orleukocytes
B. Pseudo membranous colitis -severe diarrhea,fever, stools containing shreds of mucousmembrane and large # of neutrophils. CI. difficileproduces a toxin which is cytotoxic to mucosalcells.
TET like other antimicrobial agents administeredorally may lead to development supra infections,usually due to strains of bacteria or yeast resistantto these agents.
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Hepatic Toxicity
Microscopic study of the liver reveals fine
vacuoles, cytoplasmic changes and an
increase in fat. Pregnant women areparticularly sensitive to TET -induced
hepatic damage. Jaundice ( increased
UREA) azotemia, acidosis, shock. (inpregnant women experiencing
pyelonephritis can be fatal)
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Renal Toxicity
TET may aggregate uremia in patients with
renal disease by I protein synthesis -
increased azotemia.Fanconi Syndrome -observed in patients
after taking outdated and degraded TET. -
clinical picture -nausea, vomiting, polyuria,polydipsia, acidosis, proteinuria, glycosuria
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Effects on TEETH
Children receiving long-or short term therapy
with TET may develop brown discoloration of
the teeth. The drug deposits in the teeth andbones probably due to its chelating property
and the formation of a TET -calcium
orthophosphate complex. This discoloration is
permanent. Avoid giving to pregnant womenand children under the age of 8.
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Other effects
Hyersensitivity Rxn -Rash, hives with
itching, itching anaphylactic rxn ( decrease
in BP, increase in HR, release of histamine,etc.)
Photoxicity -1 darkening of skin & sunburnwhen patient exposed to sunlight
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Effects on Microbial Agents
The TET possess a wide range of antimicrobial
activity against gram-positive and gram-
negative bacteria. These drugs are primarilybacteriostatic. Only multiplying microorganisms
are affected. Minocycline is usually the most
active followed by doxycycline then TET and
oxytetracycline (least active). Strains inhibitedby 4 ug/ml or less at TET are considered
sensitive.
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Therapeutic Uses
The TET has been used extensively both for
the treatment of infections diseases. Both
uses have resulted in f bacterial resistance tothese drugs. Thus the number of indications
for the use of TET has declined.
1. TET should not be used in pregnant
women and children under 8.2. Should not be given to patient with severe
liver disease.