Transcript Tetracyclines

Tetracyclines
History
The development of the tetracycline antibiotics
was the result of a systemic screening of soil
specimens collected from many parts of the
world for antibiotic-producing microorganisms.
The first of these compounds chlortetracycline
was introduced in 1948 followed by
oxytetracycline and tetracycline in 1950 and
1952 respectively.
Chemistry
The basic tetracycline structure consists of
four benzene rings with various constituents
on each ring.
The crystalline bases are faintly yellow,
odorless, slightly bitter compounds. They are
only slightly soluble in water at pH 7 but they
can form soluble sodium salts and
hydrochloride.
Mechanism of Action
The site of action of TET is the bacterial ribosome
and all TET function in the same manner. They are
bacteriostatic compounds. They inhibit protein
synthesis by binding specifically to the 30S
ribosome. This appears to prevent access of AAtRNA to the acceptor site on the mRNA-ribosome
complex; preventing the addition of AA to the
growing peptide chain.
These compounds also impair protein synthesis in
mammalian cells at high concentration. For gram (-)
bacteria, less understood for gram (+) bacteria.
Step 1 -Passive diffusion through hydrophilic
pores in the outer cell membranes.
Step 2 -Energy-dependent active transport
system that pumps all TET through the inner
cytoplasmic membrane.
Minocyline & perhaps doxycycline are more
lipophilic than the other TET and pass directly
through the lipid bilayer.
Resistance
Resistance to the TET for gram-neg and
gram-pos bacteria is mediated by inducible
plasmid [the bacteria become resistant only
after 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, thereby
preventing binding to the ribosomes.
Pharmacokinetics
Absorption:
All TET are adequately but incompletely
absorbed from the G.I. tract. The % of an oral
dose that is absorbed (when the stomach is
empty) is lowest for chlortetracycline (30%) and
highest for minocycline (~98-100%). Most
absorption takes place from the stomach and
upper small intestine (greater in a fasting state).
Absorption of TET is impaired by food in the
stomach, milk products, aluminum OH gels, Na+
bicarbonate, Ca++ & Mg++, and Fe++
preparations.
After a single oral dose peak plasma
concentration are achieved in 2-4 hours.
The mechanisms responsible for
decreased absorption for decreased
absorption appear to be chelation and
an increase in gastric pH.
Distribution
The Vd of the TET is relatively larger than
that of the body water. They are bound to
plasma protein in varying degree.
Penetration of these drugs into most tissues
and body fluids is excellent.
All TET are concentrated in the liver and
excreted by way of the bile into the intestine
from which they are partially reabsorbed
(enterohepatic circulation) Bile: serum ratio
range from 5 –lOX that of plasma.
B. CSF levels are 10 -20% of the serum
levels.
C. TET are stored in the reticuloendothelial
cells
D. TET crosses the placental barrier and
can accumulate in fetal bones, thus
delaying bone growth. They are also
excreted in breast milk.
Excretion
All the TET are excreted in the urine and the
feces, the primary route for most being the kidney.
The mechanism of renal exertion is glomerular
filtration. They will accumulate in the body in
patients with depressed renal function; EXCEPT
doxycycline -not eliminated via the same
pathways as other TET. The drug is excreted in
the feces, largely as an inactive conjugate. Thus
one of the safest of the TET for the treatment of
extrarenal infections.
Adverse Effects
TET can produce a variety of adverse
effects ranging from minor
inconvenience to life-threatening.
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)
A. Normal -loose stools do not contain blood or
leukocytes
B. Pseudo membranous colitis -severe diarrhea,
fever, stools containing shreds of mucous
membrane and large # of neutrophils. CI. difficile
produces a toxin which is cytotoxic to mucosal
cells.
TET like other antimicrobial agents administered
orally may lead to development supra infections,
usually due to strains of bacteria or yeast resistant
to these agents.
Hepatic Toxicity
Microscopic study of the liver reveals fine
vacuoles, cytoplasmic changes and an
increase in fat. Pregnant women are
particularly sensitive to TET -induced
hepatic damage. Jaundice ( increased
UREA) azotemia, acidosis, shock. (in
pregnant women experiencing
pyelonephritis can be fatal)
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
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 and
bones probably due to its chelating property
and the formation of a TET -calcium
orthophosphate complex. This discoloration is
permanent. Avoid giving to pregnant women
and children under the age of 8.
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 & sunburn
when patient exposed to sunlight
Effects on Microbial Agents
The TET possess a wide range of antimicrobial
activity against gram-positive and gramnegative bacteria. These drugs are primarily
bacteriostatic. Only multiplying microorganisms
are affected. Minocycline is usually the most
active followed by doxycycline then TET and
oxytetracycline (least active). Strains inhibited
by 4 ug/ml or less at TET are considered
sensitive.
Therapeutic Uses
The TET has been used extensively both for
the treatment of infections diseases. Both
uses have resulted in f bacterial resistance to
these 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.