TETRACYCLINES

Dr. Robert Copeland

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 tetra 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.

The mechanisms responsible for decreased absorption for decreased absorption appear to be chelation and an increase in gastric pH.

After a single oral dose peak plasma concentration are achieved in 2-4 hours.

Dose:

Oxy & TET -2-4 times/d 250 mg every 6 hour plasma concentration 3 ug/ml.

Demeclocycline -lower dose

Methacycline

Doxycycline & minocycline -even lower dose -100 mg once a day 200 mg ~ plasma conc. 3 ug/ml maintained @ 1 ug/ml for 8-12 hr

Food does not interfere with these two

TET can also be administered by the 1M and IV route but these methods are associated with some pain due to irritation.

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.

A. All TET are concentration 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 which do not contain blood or leukocytes

B. Pseudo 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 t 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.

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 & sunburn

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.