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 AA-

tRNA 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 gram-negative 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.