Tetracyclines

Tetracyclines

The tetracyclines are a group of actinomycete antibiotics tha have a broad spectrum and considerable therapeutic utility. Seven such compounds-tetracycline, oxytetracycline, chlortetracycline, demeclocycline, methacycline, doxycycline and rolitetracycline are used as medicine.

 The tetracyclines are obtained by fermentation procedures tetracy from Streptomyces species or by chemical transformations of the natural products. The important members of the group are cline derivatives of an octahydronaphthacene, a hydrocarbon that is consisted of a system of four fused rings (named tetracycline) .The first of these compounds, chlortetracycline, was introduced in 1948. Two years later oxytetracycline was obtained.

 The tetracyclines were found to be highly effective against rickettsiae, a number of gram-positive and gram-negative bacteria some of the large viruses , some intestinal amoebae and the agents responsible for lympho-granuloma , conjunctivitis and psittacosis . Therefore they are known as ‘ broad spectrum antibiotics .

The tetracycline are closely congeneric derivatives of the tetracyclic naphthalene carboxamide. Streptomyces flavovirens produces an antibiotic pillaromycin A that consists of an aglycone related to the tetracyclines with an unusal sugars .

All tetracyclines are almost stable and are absorbed adequately in gastro-intestinal tract. These amphoteric compounds are most stable in acid and least stable in alkali. The tetracycline antibiotics are usually used as the hydrochloride salts. Chlortetracycline is the least stable of these antibiotics. They form salts with acids and with bases. In neutral solutions these compounds exist mainly as zwitter ions.

Erratic and unsatisfactory absorption of the tetracyclines takes place when calcium ions and other heavy ions are present in diet or when preparations as aluminium hydroxide-containing antacids are used. Phosphate combinations may be used in tetracycline formulations to reduce the impact of heavy metal ions on absorption. Stable chelate complexes are formed by the tetracyclines with many metals such as calcium, iron and magnesium. Demeclocycline, doxycycline, and methacycline are absorbed more readily than the other tetracycline antibiotics. Their absorption is influenced to a lesser degree by food and milk. Chelation does not play a basic role in the mode of action of the tetracyclines, but it may facilitate transport of the compounds to their sites of action. They act principally by interference with protein synthesis.

Tetracyclines are often considered the antibiotics of choice for treatment of brucellosis, cholera, relapsing fever, and infections caused by Chlamydia, Mycoplasma, Yersinia (Pasteurella), rickettsia, and a large number of other infections.

The usual serum half-lives of various tetracyclines are 5-6 hours for chlortetracycline, 8-9 hours for tetracycline, 12-14 hours for demeclocycline and methacycline and 17-19 hours for doxycycline and minocycline. These compounds are eliminated by biliary excretion, glomerular filtration, and metabolism. There is extensive enterohepatic recycling of the tetracycline antibiotics. About 20-50% of the tetracyclines are eliminated by urinal. The rate of renal clearance is slowest for doxycycline and minocycline. Metabolic degradation of these antibiotics is relatively insignificant. Resistance to the tetracyclines developed slowly and becomes a serious problem with pneumococci, straphylococci, streptococci, and some gram-negative pathogens.

The amphoteric antibiotics will crystallize out of aqueous solutions of their salts. The hydrochloride salts are used most commonly for oral administration in the form of capsules due to their bitter taste. Water-soluble salts may be obtained from bases such as sodium or potassium hydroxides. These salts are not stable in aqueous solutions. Water-insoluble salts are

formed with divalent and polyvalent metals. Such calcium salts are used to prepare tasteless suspensions for liquid oral dosage forms.

An interesting property of the tetracyclines is to form epimers, called epi-tetracyclines at carbon atom 4 in solutions of intermediate pH range. Under the influence of the acidic conditions, an equilibrium is maintained within 24-hours containing about equal amounts of the isomers. The 4epitetracyclines have been isolated and identified.

Strong acids and bases react with the tetracyclines having a hydroxy group of C-6, causing a loss in activity through modification of the C-ring. Strong acids produce dehydration creating unsaturation at C-6, C-5a, which induces a shift in the position of the double bond between carbons C-1 la and C-2 to a position between carbon atoms C-1 1 and C-1 la. In this way the more energetically favoured resonant system of the naphthalene group is formed. In th presence of bases, a reaction between the 6-hydroxyl group and the ketone group at C-1 ) takes place, the bond between C-1 l and C-1 la is cleaved and the lactone ring, found in the inactive isotetracyclines, is formed.

The relationships between chemical structure and the biological activity of tetracyclines have been studied. The substitution on the 5 and 7 carbon atoms and hydroxyl substitution on the 6 carbon atom are not essential for activity. Removal of the 4-dimethylamino group causes a loss of about 75 per cent of the antibiotic effect of the parent tetracyclines. The 4-epitetracyclines are less active than the dedimethyl-amino compounds, suggesting structural conformations in this area may be important in fitting the molecule on a possible enzyme site. A substantial loss of activity by epimerization at carbon atom 5a takes place. Dehydrogenation to form a double bond between carbon atoms 5a and l l a produces a marked decrease in activity. In the same way, dehydration by strong acids of the 6 hydroxyl group and a hydrogen on the 5a carbon atom produces inactive anhydrotetracycline that has an aromatic C ring. Substitution of bulky groups for one of the hydrogens on the amide nitrogen does not cause any appreciable loss in activity .