tetracycline s

7/31/2019 Tetracycline s

1/21

Tetracyclines


2/21


3/21

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.


4/21


5/21

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.


6/21

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.


7/21

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.


8/21

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.


9/21

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.


10/21

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.


11/21

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.


12/21

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.


13/21

Adverse Effects

TET can produce a variety of adverse

effects ranging from minorinconvenience to life-threatening.


14/21

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)


15/21

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.


16/21

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)


17/21

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


18/21

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.


19/21

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


20/21

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.


21/21

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.

tetracycline s

Documents